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1
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Tagawa K, Maruo Y, Mimura Y, Ikushiro S. Effects of common genetic variants of human uridine diphosphate glucuronosyltransferase subfamilies on irinotecan glucuronidation. Toxicol Mech Methods 2023; 33:197-205. [PMID: 35930428 DOI: 10.1080/15376516.2022.2109229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
The adverse effects (diarrhea and neutropenia) of irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) are associated with genetic variants of uridine diphosphate glucuronosyltransferase 1A subfamilies (UGT1As). UGT1As are enzymes that metabolize the active form of irinotecan, 7-ethyl-10 hydroxycamptothecin (SN-38), by glucuronidation in the liver. They are widely known as predictive factors of severe adverse effects, such as neutropenia and diarrhea. Some studies have suggested that variants of UGT1As affect SN-38 glucuronidation activities, thus exerting severe adverse effects. We aimed to identify UGT1A isoforms that show SN-38 glucuronidation activity and determine the relationship between UGT1A variants and SN-38 glucuronidation in vitro. We found that UGT1A1 and UGT1A6-UGT1A10 displayed SN-38 glucuronidation activity. Among these, UGT1A1 was the most active. Furthermore, the variants of these isoforms showed decreased SN-38 glucuronidation activity. In our study, we compared the different variants of UGT1As, such as UGT1A1.6, UGT1A1.7, UGT1A1.27, UGT1A1.35, UGT1A7.3, UGT1A8.4, UGT1A10M59I, and UGT1A10T202I, to determine the differences in the reduction of glucuronidation. Our study elucidates the relationship between UGT1A variants and the level of glucuronidation associated with each variant. Therefore, testing can be done before the initiation of irinotecan treatment to predict potential toxicities and adverse effects.
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Affiliation(s)
- Kouji Tagawa
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
| | - Yoshihiro Maruo
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
| | - Yu Mimura
- Department of Pediatrics, Toyosato Hospital, Shiga, Japan
| | - Shinichi Ikushiro
- Department of Biotechnology, Toyama Prefectural University, Toyama, Japan
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姚 璇, 钟 丹, 彭 运. [ UGT1A1 gene mutations in Chinese Dong neonates in Sanjiang, Guangxi]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2022; 24:792-796. [PMID: 35894195 PMCID: PMC9336619 DOI: 10.7499/j.issn.1008-8830.2202127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/31/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVES To study the characteristics of UGT1A1 gene mutations in Dong neonates in Sanjiang County of Liuzhou and its association with the pathogenesis of hyperbilirubinemia in Dong neonates. METHODS A prospective analysis was performed on 84 neonates who were diagnosed with unexplained hyperbilirubinemia in the Department of Neonatology, Sanjiang County People's Hospital, from January 2021 to January 2022. Sixty healthy neonates born during the same period were enrolled as the control group. Peripheral blood genomic DNA was extracted for both groups, and UGT1A1 exon 1 was amplified by PCR and sequenced. RESULTS In the case group, 33 neonates were found to have G71R missense mutation, with a mutation rate of 39%. The case group had a significantly higher frequency of A allele than the healthy control group (21% vs 10%, P<0.05). The risk of hyperbilirubinemia in Dong neonates carrying G71R missense mutation was 2.588 times as high as that in healthy neonates carrying wild-type UGT1A1 gene (P<0.05). Hardy-Weinberg equilibrium testing showed that the UGT1A1 G71R locus was in genetic equilibrium in both groups (P>0.05). CONCLUSIONS UGT1A1 G71R mutation is a high-frequency gene mutation type in Dong neonates in Sanjiang County, and G71R missense mutation is associated with hyperbilirubinemia in Dong neonates.
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Kaliannan K, Donnell SO, Murphy K, Stanton C, Kang C, Wang B, Li XY, Bhan AK, Kang JX. Decreased Tissue Omega-6/Omega-3 Fatty Acid Ratio Prevents Chemotherapy-Induced Gastrointestinal Toxicity Associated with Alterations of Gut Microbiome. Int J Mol Sci 2022; 23:5332. [PMID: 35628140 PMCID: PMC9140600 DOI: 10.3390/ijms23105332] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/02/2022] [Accepted: 05/06/2022] [Indexed: 02/04/2023] Open
Abstract
Gastrointestinal toxicity (GIT) is a debilitating side effect of Irinotecan (CPT-11) and limits its clinical utility. Gut dysbiosis has been shown to mediate this side effect of CPT-11 by increasing gut bacterial β-glucuronidase (GUSB) activity and impairing the intestinal mucosal barrier (IMB). We have recently shown the opposing effects of omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) on the gut microbiome. We hypothesized that elevated levels of tissue n-3 PUFA with a decreased n-6/n-3 PUFA ratio would reduce CPT-11-induced GIT and associated changes in the gut microbiome. Using a unique transgenic mouse (FAT-1) model combined with dietary supplementation experiments, we demonstrate that an elevated tissue n-3 PUFA status with a decreased n-6/n-3 PUFA ratio significantly reduces CPT-11-induced weight loss, bloody diarrhea, gut pathological changes, and mortality. Gut microbiome analysis by 16S rRNA gene sequencing and QIIME2 revealed that improvements in GIT were associated with the reduction in the CPT-11-induced increase in both GUSB-producing bacteria (e.g., Enterobacteriaceae) and GUSB enzyme activity, decrease in IMB-maintaining bacteria (e.g., Bifidobacterium), IMB dysfunction and systemic endotoxemia. These results uncover a host-microbiome interaction approach to the management of drug-induced gut toxicity. The prevention of CPT-11-induced gut microbiome changes by decreasing the tissue n-6/n-3 PUFA ratio could be a novel strategy to prevent chemotherapy-induced GIT.
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Affiliation(s)
- Kanakaraju Kaliannan
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; (K.K.); (B.W.); (X.-Y.L.)
| | - Shane O. Donnell
- School of Microbiology, University College Cork, T12 K8AF Cork, Ireland; (S.O.D.); (C.S.)
- Teagasc Moorepark Food Research Centre, Fermoy, P61 C996 Co. Cork, Ireland
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland;
| | - Kiera Murphy
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland;
| | - Catherine Stanton
- School of Microbiology, University College Cork, T12 K8AF Cork, Ireland; (S.O.D.); (C.S.)
- Teagasc Moorepark Food Research Centre, Fermoy, P61 C996 Co. Cork, Ireland
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland;
| | - Chao Kang
- Department of Nutrition, The General Hospital of Western Theater Command, Chengdu 610000, China;
| | - Bin Wang
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; (K.K.); (B.W.); (X.-Y.L.)
| | - Xiang-Yong Li
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; (K.K.); (B.W.); (X.-Y.L.)
| | - Atul K. Bhan
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA;
| | - Jing X. Kang
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; (K.K.); (B.W.); (X.-Y.L.)
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4
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Chen H, Zhong D, Gao Z, Wu X. Effect of the genetic mutant G71R in uridine diphosphate-glucuronosyltransferase 1A1 on the conjugation of bilirubin. Open Life Sci 2022; 17:221-229. [PMID: 35415244 PMCID: PMC8934855 DOI: 10.1515/biol-2022-0021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 12/18/2021] [Accepted: 01/03/2022] [Indexed: 12/03/2022] Open
Abstract
We aimed to investigate the effect of the genetic mutant G71R (c. 211G > A) in uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) on the glucuronidation of unconjugated bilirubin. The UGT1A1 wild-type and mutant G71R gene sequences were inserted into the lentiviral vector GV358 plasmid and then transfected into COS-7 cells. Real-time polymerase chain reaction and western blot analyses were used to determine mRNA and protein expression levels of UGT1A1, respectively. High-performance liquid chromatography was used to quantitate the levels of conjugated bilirubin. The results showed no significant difference in the mRNA and protein expression levels between the UGT1A1 wild-type and G71R homozygous and heterozygous mutants. The level of conjugated bilirubin reached a maximum in wild-type UGT1A1-transfected COS-7 cells. However, relative to the UGT1A1 wild-type, conjugated bilirubin concentrations were 71 and 22% with G71R heterozygous- and G71R homozygous-transfected COS-7 cells, respectively. In conclusion, we successfully established in vitro cell models of the UGT1A1 wild-type and the G71R homozygous and heterozygous mutants using a lentiviral vector. Furthermore, the catalytic activity for unconjugated bilirubin was lower in the mutant G71R than the UGT1A1 wild-type enzyme, and a weaker effect was observed in the homozygote.
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Affiliation(s)
- Hong Chen
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University , No. 6 Shuangyong Road , Nanning 530021 , Guangxi , China
| | - Danni Zhong
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University , No. 6 Shuangyong Road , Nanning 530021 , Guangxi , China
| | - Zongyan Gao
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University , No. 6 Shuangyong Road , Nanning 530021 , Guangxi , China
| | - Xiaojing Wu
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University , No. 6 Shuangyong Road , Nanning 530021 , Guangxi , China
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5
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Miyauchi Y, Takechi S, Ishii Y. Functional Interaction between Cytochrome P450 and UDP-Glucuronosyltransferase on the Endoplasmic Reticulum Membrane: One of Post-translational Factors Which Possibly Contributes to Their Inter-Individual Differences. Biol Pharm Bull 2021; 44:1635-1644. [PMID: 34719641 DOI: 10.1248/bpb.b21-00286] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cytochrome P450 (P450) and uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) catalyze oxidation and glucuronidation in drug metabolism, respectively. It is believed that P450 and UGT work separately because they perform distinct reactions and exhibit opposite membrane topologies on the endoplasmic reticulum (ER). However, given that some chemicals are sequentially metabolized by P450 and UGT, it is reasonable to consider that the enzymes may interact and work cooperatively. Previous research by our team detected protein-protein interactions between P450 and UGT by analyzing solubilized rat liver microsomes with P450-immobilized affinity column chromatography. Although P450 and UGT have been known to form homo- and hetero-oligomers, this is the first report indicating a P450-UGT association. Based on our previous study, we focused on the P450-UGT interaction and reported lines of evidence that the P450-UGT association is a functional protein-protein interaction that can alter the enzymatic capabilities, including enhancement or suppression of the activities of P450 and UGT, helping UGT to acquire novel regioselectivity, and inhibiting substrate binding to P450. Biochemical and molecular bioscientific approaches suggested that P450 and UGT interact with each other at their internal hydrophobic domains in the ER membrane. Furthermore, several in vivo studies have reported the presence of a functional P450-UGT association under physiological conditions. The P450-UGT interaction is expected to function as a novel post-translational factor for inter-individual differences in the drug-metabolizing enzymes.
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Affiliation(s)
- Yuu Miyauchi
- Laboratory of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Sojo University.,Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University
| | - Shinji Takechi
- Laboratory of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Sojo University
| | - Yuji Ishii
- Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University.,Laboratory of Molecular Life Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University
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6
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Parvez MM, Basit A, Jariwala PB, Gáborik Z, Kis E, Heyward S, Redinbo MR, Prasad B. Quantitative Investigation of Irinotecan Metabolism, Transport, and Gut Microbiome Activation. Drug Metab Dispos 2021; 49:683-693. [PMID: 34074730 PMCID: PMC8407663 DOI: 10.1124/dmd.121.000476] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 05/24/2021] [Indexed: 01/01/2023] Open
Abstract
The anticancer drug irinotecan shows serious dose-limiting gastrointestinal toxicity regardless of intravenous dosing. Although enzymes and transporters involved in irinotecan disposition are known, quantitative contributions of these mechanisms in complex in vivo disposition of irinotecan are poorly understood. We explained intestinal disposition and toxicity of irinotecan by integrating 1) in vitro metabolism and transport data of irinotecan and its metabolites, 2) ex vivo gut microbial activation of the toxic metabolite SN-38, and 3) the tissue protein abundance data of enzymes and transporters relevant to irinotecan and its metabolites. Integration of in vitro kinetics data with the tissue enzyme and transporter abundance predicted that carboxylesterase (CES)-mediated hydrolysis of irinotecan is the rate-limiting process in the liver, where the toxic metabolite formed is rapidly deactivated by glucuronidation. In contrast, the poor SN-38 glucuronidation rate as compared with its efficient formation by CES2 in the enterocytes is the key mechanism of the intestinal accumulation of the toxic metabolite. The biliary efflux and organic anion transporting polypeptide-2B1-mediated enterocyte uptake can also synergize buildup of SN-38 in the enterocytes, whereas intestinal P-glycoprotein likely facilitates SN-38 detoxification in the enterocytes. The higher SN-38 concentration in the intestine can be further nourished by β-d-glucuronidases. Understanding the quantitative significance of the key metabolism and transport processes of irinotecan and its metabolites can be leveraged to alleviate its intestinal side effects. Further, the proteomics-informed quantitative approach to determine intracellular disposition can be extended to determine susceptibility of cancer cells over normal cells for precision irinotecan therapy. SIGNIFICANCE STATEMENT: This work provides a deeper insight into the quantitative relevance of irinotecan hydrolysis (activation), conjugation (deactivation), and deconjugation (reactivation) by human or gut microbial enzymes or transporters. The results of this study explain the characteristic intestinal exposure and toxicity of irinotecan. The quantitative tissue-specific in vitro to in vivo extrapolation approach presented in this study can be extended to cancer cells.
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Affiliation(s)
- Md Masud Parvez
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.)
| | - Abdul Basit
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.)
| | - Parth B Jariwala
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.)
| | - Zsuzsanna Gáborik
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.)
| | - Emese Kis
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.)
| | - Scott Heyward
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.)
| | - Matthew R Redinbo
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.)
| | - Bhagwat Prasad
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.)
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7
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Association of UGT1A1*6 polymorphism with irinotecan-based chemotherapy reaction in colorectal cancer patients: a systematic review and a meta-analysis. Biosci Rep 2021; 40:226428. [PMID: 32936306 PMCID: PMC7578622 DOI: 10.1042/bsr20200576] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 08/25/2020] [Accepted: 09/10/2020] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths across the world. Irinotecan (IRI) is commonly used to treat CRC, and IRI-based chemotherapy is linked with adverse reaction and the efficacy of the treatment regimen. The gene UGT1A1 plays a central role in the IRI metabolic pathway. A polymorphism UGT1A1*6 has been widely researched which may be related to response of IRI-based chemotherapy in CRC. All relevant studies were strictly searched from PubMed, Embase, Cochrane Library and Web of Science databases to explore the associations between UGT1A1*6 and response of IRI-based chemotherapy with CRC. Nine articles comprising 1652 patients were included in the final combination. Meta-analysis showed G allele or GG had a lower risk of severe late-onset diarrhea compared with A/AA in allele model and homozygote model (G vs. A: OR = 0.53, 95% CI: 0.28–0.99, P=0.05; GG vs. AA: OR = 0.48, 95% CI: 0.23–0.99, P=0.05), no significant association was observed in other models. In addition, a significant association between UGT1A1*6 and neutropenia was observed in all models (G vs. A: OR = 0.57, 95% CI: 0.46–0.71, P=0.00; GG vs. AA: OR = 0.28, 95% CI: 0.17–0.45, P=0.01; GA vs. AA: OR = 0.42, 95% CI: 0.26–0.70, P=0.00; GG+GA vs. AA: OR = 0.32, 95% CI: 0.20–0.52, P=0.00; GG vs. AA+GA: OR = 0.40, 95% CI: 0.22–0.71, P=0.00), whereas, no relationship was found between UGT1A1*6 and clinical response among the different genotypes. UGT1A1*6 may be considered as a biomarker for IRI-based chemotherapy in CRC.
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8
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Zhu X, Zhu J, Sun F, Zhen Z, Zhou D, Lu S, Huang J, Que Y, Zhang L, Cai R, Wang J, Zhang Y. Influence of UGT1A1 *6/*28 Polymorphisms on Irinotecan-Related Toxicity and Survival in Pediatric Patients with Relapsed/Refractory Solid Tumors Treated with the VIT Regimen. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2021; 14:369-377. [PMID: 33790625 PMCID: PMC8001723 DOI: 10.2147/pgpm.s292556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 03/02/2021] [Indexed: 11/23/2022]
Abstract
Objective The association between UGT1A1*6/*28 polymorphisms and treatment outcomes of irinotecan in children remains unknown. This retrospective study investigated the influence of UGT1A1*6/*28 polymorphisms on irinotecan toxicity and survival of pediatric patients with relapsed/refractory solid tumors. Methods The present study enrolled a total of 44 patients aged younger than 18 years at Sun Yat-sen University Cancer Center between 2014 and 2017. Results There were 26 boys and 18 girls; the median age at first VIT course was six years (range: 1-18 years). The tumor types included neuroblastoma (n = 25), rhabdomyosarcoma (n = 11), Wilm's tumor (n = 4), medulloblastoma (n = 2), and desmoplastic small round cell tumor (n = 2). Overall, 203 courses of VIT regimens were prescribed. Neither UGT1A1*6 nor *28 polymorphisms were associated with the incidence rates of severe (grade III-IV) irinotecan-related toxicities, but tended to reduce the patient overall survival (UGT1A1*6, P = 0.146; UGT1A1*28, P = 0.195). Moreover, patients with mutant UGT1A1*6 genotypes were more likely to develop grade I-IV irinotecan-related diarrhea (P = 0.043) and anemia (P = 0.002). Overall, the UGT1A1*28 polymorphism may play a protective role against irinotecan-related diarrhea and abdominal pain. Conclusion In relapsed/refractory pediatric solid tumors, the UGT1A1*6 polymorphism was a risk factor of irinotecan-related diarrhea and anemia. The UGT1A1*28 polymorphism may serve a protective role in irinotecan-related abdominal pain and diarrhea. Both mutations had a tendency to be risk factors for survival. Nevertheless, prospective studies are required to verify such conclusions.
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Affiliation(s)
- Xiaoqin Zhu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Jia Zhu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Feifei Sun
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Zijun Zhen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Dalei Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Suying Lu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Junting Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Yi Que
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Lian Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Ruiqing Cai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Juan Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Yizhuo Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.,Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
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9
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Okamoto H, Oitate M, Hagihara K, Shiozawa H, Furuta Y, Ogitani Y, Kuga H. Pharmacokinetics of trastuzumab deruxtecan (T-DXd), a novel anti-HER2 antibody-drug conjugate, in HER2-positive tumour-bearing mice. Xenobiotica 2020; 50:1242-1250. [PMID: 32306807 DOI: 10.1080/00498254.2020.1755909] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Trastuzumab deruxtecan (T-DXd, DS-8201a) is an antibody-drug conjugate (ADC), comprising an anti-HER2 antibody (Ab) at a drug-to-Ab ratio of 7-8 with the topoisomerase I inhibitor DXd. In this study, we investigated the pharmacokinetics (PK), biodistribution, catabolism, and excretion profiles of T-DXd in HER2-positive tumour-bearing mice.Following intravenous (iv) administration of T-DXd, the PK profiles of T-DXd and total Ab (the sum of conjugated and unconjugated Ab) were almost similar, indicating that the linker is stable during circulation. Biodistribution studies using radiolabelled T-DXd demonstrated tumour-specific distribution and long-term retention. DXd was the main catabolite released from T-DXd in tumours, with exposure levels at least five times higher than those in normal tissues and seven times higher than those achieved by non-targeted control ADC. Following iv administration of DXd, it was rapidly cleared from the circulation (T1/2; 1.35 h) and excreted mainly through faeces as its intact form.The PK profiles reveal that T-DXd effectively delivers the expected payload, DXd, to tumours, while minimising payload exposure to the systemic circulation and normal tissues. The released DXd is rapidly cleared from systemic circulation, presumably via the bile with negligible metabolism, and excreted through the faeces.
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Affiliation(s)
- Hiromi Okamoto
- Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Masataka Oitate
- Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Katsunobu Hagihara
- Biomarker & Translational Research Department, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Hideyuki Shiozawa
- Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Yoshitake Furuta
- Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Yusuke Ogitani
- Oncology Research Laboratories II, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Hiroshi Kuga
- Modality Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan
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10
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A genome-wide association study on liver enzymes in Korean population. PLoS One 2020; 15:e0229374. [PMID: 32084209 PMCID: PMC7034899 DOI: 10.1371/journal.pone.0229374] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 02/05/2020] [Indexed: 12/20/2022] Open
Abstract
Background Although genetic features vary across ethnicities, few genome-wide association studies (GWAS) have reported the genetic determinants of liver enzyme expression. This study was aimed to evaluate the associations of genome-wide single nuclear polymorphisms (SNPs) with the liver enzymes in a Korean population. Methods We performed a GWAS to identify genetic loci influencing liver function, as measured by concentrations of alkaline phosphatase (ALP), alanine transaminase (ALT), gamma-glutamyl transferase (GGT) and total bilirubin (BIL) in in Korean study participants. Results A total of 6,488 subjects (4,457 in the discovery and 2,031 in the validation set) were included. The mean subject age was 50.0±10.6 years (male, 53.7%). Among a total of 546,738 SNPs tested, rs651007 and rs579459 located in the ABO gene showed strong associations with ALP (P = 1.63×10−8 and 5.61×10−8, respectively [discovery set]; P = 4.08×10−15 and 9.92×10−16, respectively [validation set]). Additionally, rs5751901 and rs2006092, which are located in the GGT1 gene, showed strong associations with GGT (P = 6.44×10−15 and 1.26×10−15, respectively [discovery set]; P = 4.13×10−10 and 5.15×10−11, respectively [validation set]). Among the 13 SNPs that showed genome-wide significance with total bilirubin levels, rs10929302 and rs6742078 showed the most significant association (P = 3.08×10−64 and 2.05×10−62, respectively [discovery set]; P = 1.33×10−116 and 2.24×10−118, respectively [validation set]). No genome-wide significant associations was found for ALT. Conclusions We demonstrated that ABO, GGT1 and UGT1A family were associated with ALP, GGT and BIL, respectively in Korean population. These findings differ from reported results in GWAS in European populations in terms of associated genes and locations, suggesting different genetic mechanisms of liver enzyme regulation according to ethnicity.
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11
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Cho IR, Kang H, Jo JH, Lee HS, Chung MJ, Park JY, Park SW, Song SY, An C, Park MS, Bang S. FOLFIRINOX vs gemcitabine/nab-paclitaxel for treatment of metastatic pancreatic cancer: Single-center cohort study. World J Gastrointest Oncol 2020; 12:182-194. [PMID: 32104549 PMCID: PMC7031147 DOI: 10.4251/wjgo.v12.i2.182] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 12/19/2019] [Accepted: 12/30/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND FOLFIRINOX and gemcitabine plus nab-paclitaxel (Gem + nabPTX) were recently introduced for metastatic pancreatic cancer treatment. However, studies that compared these two regimens and studies in Asian populations are lacking. AIM To compare the treatment outcomes of FOLFIRINOX and Gem + nabPTX regimen for metastatic pancreatic cancer treatment in Korean population. METHODS Patients with metastatic or recurrent pancreatic cancer treated with FOLFIRINOX (n = 86) or Gem + nabPTX (n = 81) as the first-line since January 2015 were identified using the Severance Hospital Pancreatic Cancer Cohort Registry. Treatment efficacy, treatment-related adverse events and economic aspects were compared. RESULTS Patients in the FOLFIRINOX group were significantly younger (54 vs 65 years; P < 0.001) and had better performance statuses at diagnosis. The median overall survival (10.7 vs 12.1 mo; P = 0.157), progression-free survival (8.0 vs 8.4 mo; P = 0.134), and objective response rates (33.7% vs 46.9%; P = 0.067) were not significantly different when compared with Gem + nabPTX group. Grade ≥ 3 neutropenia and gastrointestinal adverse events were more common in the FOLFIRINOX group. The drug costs of both regimens were similar. CONCLUSION Treatment efficacy and economic burdens were comparable between the two regimens. But, the details of adverse event were different. Gem + nabPTX regimen might be considered preferentially in certain conditions.
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Affiliation(s)
- In Rae Cho
- Department of Internal Medicine, International Saint Mary’s Hospital, Catholic Kwandong University College of Medicine, Incheon 22711, South Korea
- Department of Medicine, Yonsei University Graduate School, 50-1 Yonsei-ro, Seoul 03722, South Korea
| | - Huapyong Kang
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul 03722, South Korea
| | - Jung Hyun Jo
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul 03722, South Korea
| | - Hee Seung Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul 03722, South Korea
| | - Moon Jae Chung
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul 03722, South Korea
| | - Jeong Youp Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul 03722, South Korea
| | - Seung Woo Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul 03722, South Korea
| | - Si Young Song
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul 03722, South Korea
| | - Chansik An
- Department of Radiology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul 03722, South Korea
| | - Mi-Suk Park
- Department of Radiology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul 03722, South Korea
| | - Seungmin Bang
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seoul 03722, South Korea
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12
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Affiliation(s)
- Glyn Steventon
- Consultant in ADMET, England, United Kingdom of Great Britain and Northern Ireland
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13
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Lam YWF. Principles of Pharmacogenomics. Pharmacogenomics 2019. [DOI: 10.1016/b978-0-12-812626-4.00001-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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14
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Cheng KW, Tseng CH, Tzeng CC, Leu YL, Cheng TC, Wang JY, Chang JM, Lu YC, Cheng CM, Chen IJ, Cheng YA, Chen YL, Cheng TL. Pharmacological inhibition of bacterial β-glucuronidase prevents irinotecan-induced diarrhea without impairing its antitumor efficacy in vivo. Pharmacol Res 2019; 139:41-49. [PMID: 30391354 DOI: 10.1016/j.phrs.2018.10.029] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 10/13/2018] [Accepted: 10/30/2018] [Indexed: 12/27/2022]
Abstract
Irinotecan (CPT-11), a first-line chemotherapy for advanced colorectal cancer, causes serious diarrhea in patients receiving treatment. The underlying mechanism has been shown that the active metabolite of CPT-11, SN-38, is metabolized to the inactive metabolite SN-38 glucuronide (SN-38 G) during hepatic glucuronidation, and subsequently is exported into the intestine, where SN-38 G is hydrolyzed by bacterial β-glucuronidase (βG) to be SN-38, thus leading to intestinal toxicity. Thus, inhibition of the intestinal bacterial βG activity is expected to prevent CPT-11-induced diarrhea. However, the effects of such inhibition on serum pharmacokinetics of SN-38, the key determinant of CPT-11 treatment, are uncertain. Here, we determined the effects of a potent E. coli βG (eβG)-specific inhibitor pyrazolo[4,3-c]quinoline derivative (TCH-3562) for the potential use in preventing CPT-11-induced diarrhea. TCH-3562 exhibited efficacious inhibitory potency of endogenous βG activity in two anaerobes, Eubacteriumsp. and Peptostreptococcus anaerobius. Oral administration of TCH-3562 also effectively reduced the bacterial βG activity in mice intestine. Moreover, pharmacokinetic analysis of TCH-3562 revealed a relatively low amount of TCH-3562 was detected in the plasma whereas the majority of TCH-3562 was found in the feces. Importantly, co-treatment of CPT-11 and TCH-3562 did not decrease active SN-38 level in mice plasma. Finally, we established that TCH-3562 as an adjuvant treatment showed protective effects on CPT-11-induced diarrhea and had no negative effects on the therapeutic efficacy of CPT-11 in tumor-bearing mice. Therefore, inhibition of the intestinal bacterial βG activity by the specific inhibitor, TCH-3562, is promising to prevent CPT-11-induced diarrhea while maintaining its anti-tumor efficacy that may have clinical potentials for the treatment with CPT-11.
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Affiliation(s)
- Kai-Wen Cheng
- Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chih-Hua Tseng
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Pharmacy, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 807, Taiwan
| | - Cherng-Chyi Tzeng
- Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yu-Lin Leu
- Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan
| | - Ta-Chun Cheng
- Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Jaw-Yuan Wang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Jia-Ming Chang
- Department of Animal Pharmacology, Development Center for Biotechnology, New Taipei City 221, Taiwan; Preclinical Animal Pharmacology Testing Center, National Research Program, National Research Program, New Taipei City 221, Taiwan
| | - Yun-Chi Lu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chiu-Min Cheng
- Department and Graduate Institute of Aquaculture, National Kaohsiung University of Science and Technology, Kaohsiung 807, Taiwan
| | - I-Ju Chen
- Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yi-An Cheng
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yeh-Long Chen
- Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Tian-Lu Cheng
- Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Biomedical and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
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15
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Paulík A, Nekvindová J, Filip S. Irinotecan toxicity during treatment of metastatic colorectal cancer: focus on pharmacogenomics and personalized medicine. TUMORI JOURNAL 2018; 106:87-94. [PMID: 30514181 DOI: 10.1177/0300891618811283] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Colorectal cancer, one of the most frequent types of cancer worldwide, has a high mortality rate. Irinotecan (CPT-11) has been approved for the treatment of advanced or metastatic disease either as a single agent or, more commonly, as part of combined chemotherapeutic regimens. Treatment with irinotecan is often accompanied by severe toxicity (e.g. neutropenia and diarrhea) that can result in treatment interruption or cessation, thus jeopardizing the patient's prognosis and quality of life. Irinotecan is bioactivated into its metabolite SN-38, which is subsequently detoxified by uridine diphosphate-glucuronosyl transferases (mainly UGT1A1). Further, ABC transporters (i.e. ABCB1, ABCC1-ABCC6, and ABCG2) are responsible for drug efflux into bile and urine whereas OATP transporters (SLCO1B1) enable its influx from blood into hepatocytes. Genetic polymorphisms in these enzymes/pumps may result in increased systemic SN-38 level, directly correlating with toxicity. Contemporary research is focused on the clinical implementation of genetic screenings for validated gene variations prior to treatment onset, allowing tailored individual doses or treatment regimens.
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Affiliation(s)
- Adam Paulík
- Charles University, Faculty of Medicine in Hradec Králové, University Hospital Hradec Králové, Department of Oncology and Radiotherapy, Czech Republic
| | - Jana Nekvindová
- University Hospital Hradec Králové, Institute of Clinical Biochemistry and Diagnostics, Czech Republic
| | - Stanislav Filip
- Charles University, Faculty of Medicine in Hradec Králové, University Hospital Hradec Králové, Department of Oncology and Radiotherapy, Czech Republic
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16
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Xu F, Ren X, Chen Y, Li Q, Li R, Chen Y, Xia S. Irinotecan-platinum combination therapy for previously untreated extensive-stage small cell lung cancer patients: a meta-analysis. BMC Cancer 2018; 18:808. [PMID: 30097029 PMCID: PMC6086076 DOI: 10.1186/s12885-018-4715-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 08/01/2018] [Indexed: 12/20/2022] Open
Abstract
Background There is still a debate regarding whether regimens combining irinotecan with platinum could replace regimens combining etoposide with platinum, as first-line chemotherapy for extensive-stage small cell lung cancer (ES-SCLC). We performed a meta-analysis to compare these regimens as first-line chemotherapy for ES-SCLC. Methods A literature search for randomized controlled trials was performed using the Cochrane Library, PubMed, and Embase. The inverse variance method was used to estimate summary hazard ratios and their 95% confidence intervals for overall survival and progression free survival. Relative risk was used to estimate the overall response rate, disease control rate, 1-year survival, 2-year survival, and adverse event data. Result Nine randomized controlled trials (2451 patients) were included. Regimens combining irinotecan and platinum improved overall survival, progression-free survival and overall response rate compared to combination etoposide and platinum regimens. Meanwhile, superior progression-free survival and overall response rate outcomes were observed in the Asian subgroup of patients. These patients receiving a combination irinotecan and platinum regimen experienced grade 3–4 diarrhea more frequently and experienced less hematologic toxic events than the non-Asian groups. Conclusions Our data suggest that a combination irinotecan and platinum regimen can prolong overall survival, progression-free survival and overall response rate for patients with ES-SCLC as compared to a combination etoposide and platinum regimen. And the Asian patients could benefit from irinotecan combined with platinum easier.
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Affiliation(s)
- Fei Xu
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China.,Department of Oncology, Affiliated Hospital of Hebei University of Engineering, Handan, People's Republic of China
| | - Xiaoli Ren
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yuan Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Qianxia Li
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Ruichao Li
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yu Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Shu Xia
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China.
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17
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Chen P, Zhu KW, Zhang DY, Yan H, Liu H, Liu YL, Cao S, Zhou G, Zeng H, Chen SP, Zhao XL, Yang J, Chen XP. Influence of UGT1A1 polymorphisms on the outcome of acute myeloid leukemia patients treated with cytarabine-base regimens. J Transl Med 2018; 16:197. [PMID: 30016963 PMCID: PMC6050722 DOI: 10.1186/s12967-018-1579-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 07/13/2018] [Indexed: 12/18/2022] Open
Abstract
BACKGROUNDS UDP-glucuronosyltransferase 1A subfamily (UGT1A) enzymes can inactivate cytarabine (Ara-C) by glucuronidation, and thus serves as candidate genes for interindividual difference in Ara-C response. UGT1A1 is a major UGT1A isoform expressed in human liver. METHODS UGT1A1*6 and *28 polymorphisms resulting in reduced UGT1A1 activity were genotyped in 726 adult acute myeloid leukemia (AML) patients treated with Ara-C based regimens. Influences of both polymorphisms on chemosensitivity and disease prognosis of the patients were evaluated. RESULTS After one or two courses of Ara-C based induction chemotherapy, the complete remission (CR) rate was significantly higher in patients carrying the UGT1A1*6 (77.0%) or the UGT1A1*28 (76.4%) alleles as compared with corresponding wild-type homozygotes (66.9 and 68.5%, respectively). Carriers of the UGT1A1*6 or *28 alleles showed significantly decreased risk of non-CR (OR = 0.528, 95% CI 0.379-0.737, P = 1.7 × 10-4) and better overall survival (HR = 0.787, 95% CI 0.627-0.990, P = 0.040) as compared with homozygotes for both polymorphisms. CONCLUSION Our results suggest that UGT1A1*28 and UGT1A1*6 are associated with improved clinical outcomes in Chinese AML patients treated with Ara-C.
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Affiliation(s)
- Peng Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, Hunan, People's Republic of China
| | - Ke-Wei Zhu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, Hunan, People's Republic of China
| | - Dao-Yu Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, Hunan, People's Republic of China
| | - Han Yan
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, Hunan, People's Republic of China
| | - Han Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, Hunan, People's Republic of China
| | - Yan-Ling Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, Hunan, People's Republic of China
| | - Shan Cao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, Hunan, People's Republic of China
| | - Gan Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, Hunan, People's Republic of China
| | - Hui Zeng
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Shu-Ping Chen
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Xie-Lan Zhao
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Jing Yang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China
| | - Xiao-Ping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China. .,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, Hunan, People's Republic of China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
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Sanchez-Dominguez CN, Gallardo-Blanco HL, Salinas-Santander MA, Ortiz-Lopez R. Uridine 5'-diphospho-glucronosyltrasferase: Its role in pharmacogenomics and human disease. Exp Ther Med 2018; 16:3-11. [PMID: 29896223 DOI: 10.3892/etm.2018.6184] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 11/17/2017] [Indexed: 12/18/2022] Open
Abstract
Biotransformation is an enzyme-catalyzed process in which the body converts endogenous compounds, xenobiotics and toxic substances into harmless or easily excreted metabolites. The biotransformation reactions are classified as phase I and II reactions. Uridine 5'-diphospho (UDP)-glucuronosyltransferases (UGTs) are a superfamily of phase II enzymes which have roles in the conjugation of xenobiotics or endogenous compounds, including drugs and bilirubin, with glucuronic acid to make them easier to excrete. The method the human body uses to achieve glucuronidation may be affected by a large interindividual variation due to changes in the sequences of the genes encoding these enzymes. In the last five years, the study of the genetic variants of the UGTs at a molecular level has become important due to its association with several diseases and the ability to predict adverse events due to drug metabolism. In the present review, the structure and the prominent genetic variants of the UGT1A subfamily and their metabolic and clinical implications are described.
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Affiliation(s)
- Celia N Sanchez-Dominguez
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Hugo L Gallardo-Blanco
- Department of Genetics, Faculty of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | | | - Rocio Ortiz-Lopez
- Tecnologico de Monterrey, Medical School and Health Sciences, Monterrey, Nuevo Leon 64710, Mexico
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19
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Hiratsuka M, Hirasawa N, Oshima Y, Kodama S, Miyata T, Dan T, Takatoku H, Kuribayashi H, Nakamura R, Saito Y. Points-to-consider documents: Scientific information on the evaluation of genetic polymorphisms during non-clinical studies and phase I clinical trials in the Japanese population. Drug Metab Pharmacokinet 2018; 33:141-149. [PMID: 29703433 DOI: 10.1016/j.dmpk.2018.01.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 12/05/2017] [Accepted: 01/15/2018] [Indexed: 01/11/2023]
Abstract
Pharmacotherapy shows striking individual differences in pharmacokinetics and pharmacodynamics, involving drug efficacy and adverse reactions. Recent genetic research has revealed that genetic polymorphisms are important intrinsic factors for these inter-individual differences. This pharmacogenomic information could help develop safer and more effective precision pharmacotherapies and thus, regulatory guidance/guidelines were developed in this area, especially in the EU and US. The Project for the Promotion of Progressive Medicine, Medical Devices, and Regenerative Medicine by the Ministry of Health, Labour and Welfare, performed by Tohoku University, reported scientific information on the evaluation of genetic polymorphisms, mainly on drug metabolizing enzymes and transporters, during non-clinical studies and phase I clinical trials in Japanese subjects/patients. We anticipate that this paper will be helpful in drug development for the regulatory usage of pharmacogenomic information, most notably pharmacokinetics.
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Affiliation(s)
- Masahiro Hiratsuka
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
| | - Noriyasu Hirasawa
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Yoshiteru Oshima
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Susumu Kodama
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan; National Institute of Health Sciences (NIHS), Tokyo, Japan; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Toshio Miyata
- Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Takashi Dan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
| | | | | | - Ryosuke Nakamura
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan; National Institute of Health Sciences (NIHS), Tokyo, Japan
| | - Yoshiro Saito
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan; National Institute of Health Sciences (NIHS), Tokyo, Japan
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20
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Amandito R, Putradista R, Jikesya C, Utaminingsih D, Rusin J, Rohsiswatmo R, Malik A. UGT1A1 gene and neonatal hyperbilirubinemia: a preliminary study from Bengkulu, Indonesia. BMC Res Notes 2018. [PMID: 29534743 PMCID: PMC5851072 DOI: 10.1186/s13104-018-3284-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Objective The genetic involvement in unconjugated neonatal hyperbilirubinemia has been extensively studied. Despite the high incidence of hyperbilirubinemia in Indonesia, studies are lacking. The objective of this study is to elucidate the role of polymorphism in the UGT1A1 in Neonatal Hyperbilirubinemia in Bengkulu, Indonesia. Results There were 41 neonates enrolled in the study; 30 had a total serum bilirubin level ≥ 15 mg/dL (hyperbilirubinemia neonates) while 11 has < 15 mg/dL (control neonates). Genetic mutations in Exon 1, UGT1A1*6 (c211g > a) and one in promoter region, UGT1A1*60 (c3279t > g) were determined by polymerase chain reaction–restriction fragment length polymorphism. We found 18 (60%) mutation in exon 1 in hyperbilirubinemia group and 7 (64%) in the control group with an identical allele frequency of 0.3 in both groups. We found heterozygous UGT1A1*60 4 times (13.3%) and homozygous 26 times (86.7%) in the hyperbilirubinemia group, with an identical allele frequency of 0.935 in hyperbilirubinemia and 1 in control group. This study supports the involvement of genetic factors in the development of unconjugated hyperbilirubinemia in Bengkulu population.
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Affiliation(s)
- Radhian Amandito
- M Yunus General Hospital, Jl Bhayangkara, Bengkulu City, Bengkulu, Indonesia.,Neonatal Intensive Care Unit, Pondok Indah General Hospital, Jl Metro Duta Kav. UE, Pondok Indah, Jakarta, Indonesia
| | - Raihandhana Putradista
- Division of Pharmaceutical Microbiology and Biotechnology, Faculty of Pharmacy, Universitas Indonesia, UI Depok Campus, Depok, West Java, 16424, Indonesia
| | - Clara Jikesya
- Division of Pharmaceutical Microbiology and Biotechnology, Faculty of Pharmacy, Universitas Indonesia, UI Depok Campus, Depok, West Java, 16424, Indonesia
| | - Dwi Utaminingsih
- Division of Pharmaceutical Microbiology and Biotechnology, Faculty of Pharmacy, Universitas Indonesia, UI Depok Campus, Depok, West Java, 16424, Indonesia
| | - Jumnalis Rusin
- Department of Pediatrics, M Yunus General Hospital, Jl Bhayangkara, Bengkulu City, Bengkulu, Indonesia
| | - Rinawati Rohsiswatmo
- Neonatal Intensive Care Unit, Pondok Indah General Hospital, Jl Metro Duta Kav. UE, Pondok Indah, Jakarta, Indonesia.,Division of Perinatology, Department of Pediatrics, Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jl Pangeran Diponegoro No. 71, Central Jakarta, Jakarta, Indonesia
| | - Amarila Malik
- Division of Pharmaceutical Microbiology and Biotechnology, Faculty of Pharmacy, Universitas Indonesia, UI Depok Campus, Depok, West Java, 16424, Indonesia.
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21
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Fukuda M, Okumura M, Iwakiri T, Arimori K, Honda T, Kobayashi K, Senju H, Takemoto S, Ikeda T, Yamaguchi H, Nakatomi K, Matsuo N, Mukae H, Ashizawa K. Relationship between UGT1A1*27 and UGT1A1*7 polymorphisms and irinotecan-related toxicities in patients with lung cancer. Thorac Cancer 2017; 9:51-58. [PMID: 29052349 PMCID: PMC5754284 DOI: 10.1111/1759-7714.12535] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 09/09/2017] [Accepted: 09/09/2017] [Indexed: 11/29/2022] Open
Abstract
Background The objective of this study was to evaluate the effects of gene polymorphisms, including UGT1A1*7, *27, and *29, on the safety of irinotecan therapy. Methods The eligibility criteria were: lung cancer patients scheduled to undergo irinotecan therapy, aged ≥ 20 years, with a performance status of 0–2. Thirty‐one patients were enrolled and their blood was collected and used to examine the frequency of UGT1A1*6, *7, *27, *28, and *29 polymorphisms and the concentrations of irinotecan, SN‐38, and SN‐38G after irinotecan therapy. Results The patients’ characteristics were as follows: male/female 25/6, median age 71 years (range 55–84), stage IIB/IIIA/IIIB/IV 2/6/11/12, and adenocarcinoma/squamous cell carcinoma/small cell carcinoma/other 14/10/3/4, respectively. The −/−, *6/−, *7/−, *27/−, *28/−, and *29/− UGT1A1 gene polymorphisms were observed in 10 (32%), 10 (32%), 2 (6%), 2 (6%), 7 (23%), and 0 (0%) cases, respectively. The UGT1A1*27 polymorphism occurred separately from the UGT1A1*28 polymorphism. The lowest leukocyte counts of the patients with the UGT1A1*27 and UGT1A1*6 gene polymorphisms were lower than those observed in the wild‐type patients. SN‐38 tended to remain in the blood for a prolonged period after the infusion of irinotecan in patients with UGT1A1*27 or UGT1A1*28 polymorphisms. No severe myelotoxicity was seen in the patients with UGT1A1*7. Conclusion UGT1A1*27 can occur separately from UGT1A1*28 and is related to leukopenia during irinotecan treatment. UGT1A1*7 is less relevant to irinotecan‐induced toxicities, and UGT1A1*29 seems to have little clinical impact.
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Affiliation(s)
- Minoru Fukuda
- Clinical Oncology Center, Nagasaki University Hospital, Nagasaki, Japan.,Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Manabu Okumura
- Department of Pharmacy, Faculty of Medicine, University of Miyazaki Hospital, Miyazaki, Japan
| | - Tomomi Iwakiri
- Department of Pharmacy, Faculty of Medicine, University of Miyazaki Hospital, Miyazaki, Japan
| | - Kazuhiko Arimori
- Department of Pharmacy, Faculty of Medicine, University of Miyazaki Hospital, Miyazaki, Japan
| | - Takuya Honda
- Clinical Oncology Center, Nagasaki University Hospital, Nagasaki, Japan.,Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kazuma Kobayashi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hiroaki Senju
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Shinnosuke Takemoto
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takaya Ikeda
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hiroyuki Yamaguchi
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Katsumi Nakatomi
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Nobuko Matsuo
- Department of Respiratory Medicine, Nagasaki Harbor Medical Center City Hospital, Nagasaki, Japan
| | - Hiroshi Mukae
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kazuto Ashizawa
- Clinical Oncology Center, Nagasaki University Hospital, Nagasaki, Japan.,Department of Clinical Oncology, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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22
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Pasternak AL, Ward KM, Luzum JA, Ellingrod VL, Hertz DL. Germline genetic variants with implications for disease risk and therapeutic outcomes. Physiol Genomics 2017; 49:567-581. [PMID: 28887371 PMCID: PMC5668651 DOI: 10.1152/physiolgenomics.00035.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Genetic testing has multiple clinical applications including disease risk assessment, diagnosis, and pharmacogenomics. Pharmacogenomics can be utilized to predict whether a pharmacologic therapy will be effective or to identify patients at risk for treatment-related toxicity. Although genetic tests are typically ordered for a distinct clinical purpose, the genetic variants that are found may have additional implications for either disease or pharmacology. This review will address multiple examples of germline genetic variants that are informative for both disease and pharmacogenomics. The discussed relationships are diverse. Some of the agents are targeted for the disease-causing genetic variant, while others, although not targeted therapies, have implications for the disease they are used to treat. It is also possible that the disease implications of a genetic variant are unrelated to the pharmacogenomic implications. Some of these examples are considered clinically actionable pharmacogenes, with evidence-based, pharmacologic treatment recommendations, while others are still investigative as areas for additional research. It is important that clinicians are aware of both the disease and pharmacogenomic associations of these germline genetic variants to ensure patients are receiving comprehensive personalized care.
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Affiliation(s)
- Amy L Pasternak
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan
| | - Kristen M Ward
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan
| | - Jasmine A Luzum
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan
| | - Vicki L Ellingrod
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan
| | - Daniel L Hertz
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan
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23
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Zhang X, Yin JF, Zhang J, Kong SJ, Zhang HY, Chen XM. UGT1A1*6 polymorphisms are correlated with irinotecan-induced neutropenia: a systematic review and meta-analysis. Cancer Chemother Pharmacol 2017; 80:135-149. [PMID: 28585035 DOI: 10.1007/s00280-017-3344-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2016] [Accepted: 05/02/2017] [Indexed: 01/26/2023]
Abstract
Irinotecan (IRI) chemotherapy toxicities can be severe, and may result in treatment delay, morbidity and in some rare cases death. Neutropenia is a life-threatening side effect of irinotecan, and UDP glucuronosyltransferases (UGTs) gene polymorphisms could predict the side effects in cancer patients and then reduce IRI-induced toxicity by preventative treatment or a decrease in dose. Both UGT1A1*6 and *28 were reliably demonstrated to be risk factors for IRI-induced neutropenia, with tests for both polymorphisms potentially being particularly useful in Asian cancer patients. However, some researchers reported that UGT1A1*6 could predict IRI-induced toxicities in Asian populations, controversial conclusions still remained. Thus, the association between UGT1A1*6 polymorphisms and IRI-induced severe toxicity in cancer patients is still needed to be explored. Therefore, this study aims to investigate the association between UGT1A1*6 polymorphisms and IRI-related severe neutropenia in cancer patients on a large scale. A total of 12 studies that included 746 wild genotype (G/G) cases and 394 variant genotype (G/A and A/A) cases were included on the basis of inclusion criteria. Then we assessed the methodologies quality; odds ratio (OR), risk difference (RD) and 95% confidence intervals (95% CI) were used to assess the strength of association. Overall, an increased risk of severe neutropenia in cancer patients with UGT1A1*6 polymorphisms was found. Patients with recessive models (GA + AA vs. GG) of UGT1A1*6 showed an increased risk (OR 2.03, 95% CI 1.54-2.68; RD = 0.11, P < 0.001). Specifically, the heterozygous variant of UGT1A1*6 showed an increased risk (OR 1.83, 95% CI 1.36-2.46; RD = 0.09, P < 0.001), and homozygous mutation showed also high risk (OR 2.95, 95% CI 1.83-4.75; RD = 0.18, P < 0.001) for severe neutropenia. Subgroup meta-analysis revealed that for patients harboring both heterozygous and homozygous variants, cancer types, low dose of IRI and the duration of treatment also presented comparably increased risk in suffering severe neutropenia. As for country, in China and Japan, there was a statistically increased severe neutropenia with variant genotype of UGT1A1*6 (China: GA + AA vs. GG, OR 1.83, 95% CI 1.28-2.59; RD = 0.08, P = 0.001; Japan: GA + AA vs. GG, OR 2.39, 95% CI 1.45-3.92; RD = 0.15, P = 0.001). In conclusion, in this meta-analysis, the UGT1A1*6 polymorphisms were associated with an increased risk of IRI-induced neutropenia in cancer patients, and increased incidences of severe neutropenia could be correlated with diverse regions, cancer type, low dose of IRI and the duration of treatment.
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Affiliation(s)
- Xue Zhang
- Department of Pharmacy, Third Affiliated Hospital to Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, 650118, Yunnan, People's Republic of China
| | - Jia-Fu Yin
- Department of Pharmacy, Third Affiliated Hospital to Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, 650118, Yunnan, People's Republic of China
| | - Jiao Zhang
- Department of Pathology, College of Basic Medicine, Dali University, Dali, 671000, People's Republic of China
| | - Shu-Jia Kong
- Department of Pharmacy, Third Affiliated Hospital to Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, 650118, Yunnan, People's Republic of China
| | - Hong-Yin Zhang
- Department of Pharmacy, Third Affiliated Hospital to Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, 650118, Yunnan, People's Republic of China
| | - Xue-Mei Chen
- Department of Pharmacy, Third Affiliated Hospital to Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, 650118, Yunnan, People's Republic of China.
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24
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Fukuda M, Shimada M, Kitazaki T, Nagashima S, Hashiguchi K, Ebi N, Takayama K, Nakanishi Y, Semba H, Harada T, Seto T, Okamoto I, Ichinose Y, Sugio K. Phase I study of irinotecan for previously treated lung cancer patients with the UGT1A1*28 or *6 polymorphism: Results of the Lung Oncology Group in Kyushu (LOGIK1004A). Thorac Cancer 2016; 8:40-45. [PMID: 27883280 PMCID: PMC5217920 DOI: 10.1111/1759-7714.12407] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 10/10/2016] [Accepted: 10/12/2016] [Indexed: 11/27/2022] Open
Abstract
Background Various polymorphisms have been detected in the UDP‐glucuronosyltransferase 1A (UGT1A) gene, and UGT1A1*28 and UGT1A1*6 have important effects on the pharmacokinetics of irinotecan and the risk of severe toxicities during irinotecan therapy. This study was conducted to determine the maximum tolerated dose (MTD) of irinotecan chemotherapy according to the UGT1A1 genotype in previously treated lung cancer patients with the UGT1A1*28 or UGT1A1*6 polymorphism. Methods The eligibility criteria were as follows: lung cancer patients that had previously been treated with anticancer agents other than irinotecan, possessed the UGT1A1*28 or UGT1A1*6 polymorphism (group A included *28/*28, *6/*6, and *28/*6, and group B included *28/− and *6/−), were aged ≤75 years old, had a performance score of 0–1, and exhibited adequate bone marrow function. The patients were scheduled to receive irinotecan on days 1, 8, 15, 22, 29, and 36. Results Four patients were enrolled in this trial. Two patients were determined to be ineligible. The remaining two patients, who belonged to group B, received an initial irinotecan dose of 60 mg/m2, but did not complete the planned treatment because of diarrhea and leukopenia. Thus, in group B patients, 60 mg/m2 was considered to be the MTD of irinotecan. The study was terminated in group A because of poor case recruitment. Conclusions The MTD of irinotecan for previously treated lung cancer patients that are heterozygous for the UGT1A1*28 or UGT1A1*6 gene polymorphism is 60 mg/m2.
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Affiliation(s)
- Minoru Fukuda
- Clinical Oncology Center, Nagasaki University Hospital, Nagasaki, Japan
| | - Midori Shimada
- Division of Respiratory Diseases, Department of Internal Medicine, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan
| | - Takeshi Kitazaki
- Division of Respiratory Diseases, Department of Internal Medicine, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan
| | - Seiji Nagashima
- Department of Medicine, National Hospital Organization Nagasaki Medical Center, Nagasaki, Japan
| | - Kohji Hashiguchi
- Division of Respiratory Diseases, Department of Internal Medicine, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan
| | - Noriyuki Ebi
- Department of Respiratory Oncology Medicine, Iizuka Hospital, Fukuoka, Japan
| | - Koichi Takayama
- Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoichi Nakanishi
- Research Institute for Disease of the Chest, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan
| | - Hiroshi Semba
- Department of Respiratory Medicine, Kumamoto Regional Medical Center, Kumamoto, Japan
| | - Taishi Harada
- Research Institute for Disease of the Chest, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan
| | - Takashi Seto
- Department of Thoracic Oncology, National Kyusyu Cancer Center, Fukuoka, Japan
| | - Isamu Okamoto
- Research Institute for Disease of the Chest, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan
| | - Yukito Ichinose
- Clinical Research Institute, National Kyusyu Cancer Center, Fukuoka, Japan
| | - Kenji Sugio
- Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, Oita, Japan.,Lung Oncology Group in Kyusyu, Fukuoka, Japan
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25
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Functional Study of Haplotypes in UGT1A1 Promoter to Find a Novel Genetic Variant Leading to Reduced Gene Expression. Ther Drug Monit 2016; 37:369-74. [PMID: 25478904 DOI: 10.1097/ftd.0000000000000154] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Uridine diphosphate glucuronyltransferase 1 family, A1 (UGT1A1) encodes for an enzyme that is a part of glucuronidation pathway, and a number of studies have shown that the promoter polymorphisms of UGT1A1 are associated with various diseases and drug response. In this study, we examined a possible association between UGT1A1 promoter haplotypes and the gene expression level. METHODS To identify promoter haplotype structure population, we directly sequenced the promoter region of UGT1A1 in 192 healthy Korean to identify 10 UGT1A1 promoter single-nucleotide polymorphisms (SNPs). Then, we genotyped the 10 SNPs in additional 192 non-Korean samples comprised of Chinese, Japanese, European American, and African American, and constructed haplotype structures. Furthermore, we conducted luciferase assay for the promoter SNP haplotypes to examine a possible expression change. RESULTS rs3755319C-rs2003569A-rs887829C-rs8175347(TA)6 (6.60 ± 0.15) and rs3755319A-rs2003569 G-rs887829C-rs8175347(TA)7 (2.79 ± 0.97) led to significantly lower gene expression when compared with rs3755319C-rs2003569 G-rs887829T-rs8175347(TA)6 (8.28 ± 0.60). CONCLUSIONS Our result suggests that the haplotypes in UGT1A1 promoter region can affect the expression level of the gene and drug metabolism associated with UGT1A1. Furthermore, in addition to rs8175347, rs3755319 was found to induce lower gene expression of UGT1A1.
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26
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Khatkov IE, Kagramanova AV, Zakharzhevskaya NB, Babikova EA, Generozov EV, Shcherbakov PL, Parfenov AI. [Current principles in the screening, diagnosis, and therapy of colorectal cancer]. TERAPEVT ARKH 2016; 88:90-96. [PMID: 27135106 DOI: 10.17116/terarkh201688290-96] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The data available in the literature on the prevalence of colorectal cancer (CRC), its risk factors and genetic aspects are analyzed. Basic screening tests and their diagnostic value are described. The paper indicates the importance of methods (colonoscopy, occult blood feces analysis, fecal immunochemical test, determination of molecular genetic profile of fecal enterocytes) for the early primary diagnosis of colonic epithelial tumors and techniques (echography, computed tomography, magnetic resonance imaging, positron emission tomography) that are required to specify clinical TNM staging and enable one to choose an optimal treatment policy for CRC patients owing to the estimation of tumor volume and to the diagnosis of reginal and distant metastases. It also shows that new screening methods based on the detection of molecular markers for early (premorphological) tumor stages are promising. The role of primary CRC prevention aimed at molding and maintaining a healthy lifestyle in the population is demonstrated.
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Affiliation(s)
- I E Khatkov
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
| | - A V Kagramanova
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
| | - N B Zakharzhevskaya
- Research Institute of Physicochemical Medicine, Federal Biomedical Agency of Russia, Moscow, Russia
| | - E A Babikova
- Research Institute of Physicochemical Medicine, Federal Biomedical Agency of Russia, Moscow, Russia
| | - E V Generozov
- Research Institute of Physicochemical Medicine, Federal Biomedical Agency of Russia, Moscow, Russia
| | - P L Shcherbakov
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
| | - A I Parfenov
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
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27
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Fukuda M, Suetsugu T, Shimada M, Kitazaki T, Hashiguchi K, Kishimoto J, Harada T, Seto T, Ebi N, Takayama K, Sugio K, Semba H, Nakanishi Y, Ichinose Y. Prospective study of the UGT1A1*27 gene polymorphism during irinotecan therapy in patients with lung cancer: Results of Lung Oncology Group in Kyusyu (LOGIK1004B). Thorac Cancer 2016; 7:467-72. [PMID: 27385990 PMCID: PMC4930967 DOI: 10.1111/1759-7714.12360] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Accepted: 04/05/2016] [Indexed: 11/27/2022] Open
Abstract
Background Uridine 5′‐diphospho‐glucuronosyltransferase 1A1 (UGT1A1*27) is known to impair the effect of UGT in basic research; however, little clinical investigation has been conducted. To evaluate the effect of the UGT1A1*27 polymorphism in irinotecan therapy, we conducted a prospective study. Methods Eligibility criteria included: lung cancer patients; scheduled irinotecan therapy doses of single ≥ 80, combination ≥ 50, radiation with single ≥ 50, or radiation with combination ≥ 40 mg/m2; age ≥ 20; and Eastern Cooperative Oncology Group performance score (PS) 0–2. Patients were examined for UGT1A1*28 and *6 polymorphisms and received irinotecan. When the UGT1A1*28 polymorphism was detected, a search for UGT1A1*27 was conducted. Fifty patients were enrolled, with 48 patients determined eligible. Results UGT1A1 polymorphisms *28/*28, *6/*6, *28/*6, *28/−, *6/−, −/− observed 0 (0%), 1 (2%), 1 (2%), 7 (15%), 17 (35%) and 22 (46%), respectively. UGT1A1*27 were examined in nine patients including one ineligible patient; however, no polymorphisms were found. The study ceased after interim analysis. In an evaluation of the side effects of irinotecan, patients with UGT1A1*28 and UGT1A1*6 polymorphisms had a higher tendency to experience febrile neutropenia than wild type (25% and 32% vs. 14%). Incidences of grade 3/4 leukopenia and neutropenia were significantly higher in patients with UGT1A1*28 polymorphisms compared with wild type (75% vs. 32%, P = 0.049; 75% vs. 36%, P = 0.039, respectively). Conclusion Our prospective study did not locate the UGT1A1*27 polymorphism, suggesting that UGT1A1*27 does not significantly predict severe irinotecan toxicity in cancer patients.
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Affiliation(s)
- Minoru Fukuda
- Clinical Oncology Center, Nagasaki University Hospital Nagasaki Japan
| | - Takayuki Suetsugu
- Department of Respiratory Medicine Sendai Medical Association Hospital Kagoshima Japan
| | - Midori Shimada
- Division of Respiratory Diseases, Department of Internal Medicine Japanese Red Cross Nagasaki Genbaku Hospital Nagasaki Japan
| | - Takeshi Kitazaki
- Division of Respiratory Diseases, Department of Internal Medicine Japanese Red Cross Nagasaki Genbaku Hospital Nagasaki Japan
| | - Kohji Hashiguchi
- Division of Respiratory Diseases, Department of Internal Medicine Japanese Red Cross Nagasaki Genbaku Hospital Nagasaki Japan
| | - Junji Kishimoto
- Department of Research and Development of Next Generation Medicine Kyusyu University Fukuoka Japan
| | - Taishi Harada
- Graduate School of Medical Sciences, Research Institute for Disease of the Chest Kyusyu University Fukuoka Japan
| | - Takashi Seto
- Department of Thoracic Oncology National Kyusyu Cancer Center Fukuoka Japan
| | - Noriyuki Ebi
- Department of Respiratory Oncology Medicine Iizuka Hospital Fukuoka Japan
| | - Koichi Takayama
- Department of Pulmonary Medicine Kyoto Prefectual University of Medicine Kyoto Japan
| | - Kenji Sugio
- Department of Thoracic and Breast Surgery Oita University Faculty of Medicine Oita Japan
| | - Hiroshi Semba
- Department of Respiratory Medicine Kumamoto Regional Medical Center Kumamoto Japan
| | - Yoichi Nakanishi
- Graduate School of Medical Sciences, Research Institute for Disease of the Chest Kyusyu University Fukuoka Japan
| | - Yukito Ichinose
- Clinical Research Institute, National Kyusyu Cancer Center Fukuoka Japan
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28
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Meric-Bernstam F, Brusco L, Daniels M, Wathoo C, Bailey AM, Strong L, Shaw K, Lu K, Qi Y, Zhao H, Lara-Guerra H, Litton J, Arun B, Eterovic AK, Aytac U, Routbort M, Subbiah V, Janku F, Davies MA, Kopetz S, Mendelsohn J, Mills GB, Chen K. Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol. Ann Oncol 2016; 27:795-800. [PMID: 26787237 DOI: 10.1093/annonc/mdw018] [Citation(s) in RCA: 148] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 01/08/2016] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Next-generation sequencing in cancer research may reveal germline variants of clinical significance. We report patient preferences for return of results and the prevalence of incidental pathogenic germline variants (PGVs). PATIENTS AND METHODS Targeted exome sequencing of 202 genes was carried out in 1000 advanced cancers using tumor and normal DNA in a research laboratory. Pathogenic variants in 18 genes, recommended for return by The American College of Medical Genetics and Genomics, as well as PALB2, were considered actionable. Patient preferences of return of incidental germline results were collected. Return of results was initiated with genetic counseling and repeat CLIA testing. RESULTS Of the 1000 patients who underwent sequencing, 43 had likely PGVs: APC (1), BRCA1 (11), BRCA2 (10), TP53 (10), MSH2 (1), MSH6 (4), PALB2 (2), PTEN (2), TSC2 (1), and RB1 (1). Twenty (47%) of 43 variants were previously known based on clinical genetic testing. Of the 1167 patients who consented for a germline testing protocol, 1157 (99%) desired to be informed of incidental results. Twenty-three previously unrecognized mutations identified in the research environment were confirmed with an orthogonal CLIA platform. All patients approached decided to proceed with formal genetic counseling; in all cases where formal genetic testing was carried out, the germline variant of concern validated with clinical genetic testing. CONCLUSIONS In this series, 2.3% patients had previously unrecognized pathogenic germline mutations in 19 cancer-related genes. Thus, genomic sequencing must be accompanied by a plan for return of germline results, in partnership with genetic counseling.
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Affiliation(s)
- F Meric-Bernstam
- Department of Investigational Cancer Therapeutics Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy Department of Surgical Oncology
| | - L Brusco
- Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy
| | - M Daniels
- Department of Gynecologic Oncology and Reproductive Medicine Program of Clinical Cancer Genetics
| | - C Wathoo
- Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy
| | - A M Bailey
- Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy
| | - L Strong
- Program of Clinical Cancer Genetics
| | - K Shaw
- Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy
| | - K Lu
- Department of Gynecologic Oncology and Reproductive Medicine Program of Clinical Cancer Genetics
| | - Y Qi
- Department of Bioinformatics and Computational Biology
| | - H Zhao
- Department of Bioinformatics and Computational Biology
| | - H Lara-Guerra
- Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy Department of RedSky/Biomedical Institute of the Americas, El Paso, USA
| | - J Litton
- Department of Breast Medical Oncology
| | - B Arun
- Department of Breast Medical Oncology Program of Clinical Cancer Genetics
| | | | - U Aytac
- Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy
| | | | - V Subbiah
- Department of Investigational Cancer Therapeutics
| | - F Janku
- Department of Investigational Cancer Therapeutics
| | - M A Davies
- Department of Systems Biology Department of Melanoma Medical Oncology
| | - S Kopetz
- Department of Gastrointestinal (GI) Medical Oncology, MD Anderson Cancer Center, Houston
| | - J Mendelsohn
- Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy Department of Genomic Medicine
| | - G B Mills
- Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy Department of Systems Biology
| | - K Chen
- Department of Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy Department of Bioinformatics and Computational Biology
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Hsieh YT, Lin HP, Chen BM, Huang PT, Roffler SR. Effect of Cellular Location of Human Carboxylesterase 2 on CPT-11 Hydrolysis and Anticancer Activity. PLoS One 2015; 10:e0141088. [PMID: 26509550 PMCID: PMC4624787 DOI: 10.1371/journal.pone.0141088] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 10/03/2015] [Indexed: 01/08/2023] Open
Abstract
CPT-11 is an anticancer prodrug that is clinically used for the treatment of metastatic colorectal cancer. Hydrolysis of CPT-11 by human carboxylesterase 2 (CE2) generates SN-38, a topoisomerase I inhibitor that is the active anti-tumor agent. Expression of CE2 in cancer cells is under investigation for the tumor-localized activation of CPT-11. CE2 is normally expressed in the endoplasmic reticulum of cells but can be engineered to direct expression of active enzyme on the plasma membrane or as a secreted form. Although previous studies have investigated different locations of CE2 expression in cancer cells, it remains unclear if CE2 cellular location affects CPT-11 anticancer activity. In the present study, we directly compared the influence of CE2 cellular location on substrate hydrolysis and CPT-11 cytotoxicity. We linked expression of CE2 and enhanced green fluorescence protein (eGFP) via a foot-and-mouth disease virus 2A (F2A) peptide to facilitate fluorescence-activated cell sorting to achieve similar expression levels of ER-located, secreted or membrane-anchored CE2. Soluble CE2 was detected in the medium of cells that expressed secreted and membrane-anchored CE2, but not in cells that expressed ER-retained CE2. Cancer cells that expressed all three forms of CE2 were more sensitive to CPT-11 as compared to unmodified cancer cells, but the membrane-anchored and ER-retained forms of CE2 were consistently more effective than secreted CE2. We conclude that expression of CE2 in the ER or on the membrane of cancer cells is suitable for enhancing CPT-11 anticancer activity.
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Affiliation(s)
- Yuan-Ting Hsieh
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Hsuan-Pei Lin
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Bing-Mae Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Ping-Ting Huang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Steve R. Roffler
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- * E-mail:
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Namjou B, Marsolo K, Lingren T, Ritchie MD, Verma SS, Cobb BL, Perry C, Kitchner TE, Brilliant MH, Peissig PL, Borthwick KM, Williams MS, Grafton J, Jarvik GP, Holm IA, Harley JB. A GWAS Study on Liver Function Test Using eMERGE Network Participants. PLoS One 2015; 10:e0138677. [PMID: 26413716 PMCID: PMC4586138 DOI: 10.1371/journal.pone.0138677] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 09/02/2015] [Indexed: 11/18/2022] Open
Abstract
Introduction Liver enzyme levels and total serum bilirubin are under genetic control and in recent years genome-wide population-based association studies have identified different susceptibility loci for these traits. We conducted a genome-wide association study in European ancestry participants from the Electronic Medical Records and Genomics (eMERGE) Network dataset of patient medical records with available genotyping data in order to identify genetic contributors to variability in serum bilirubin levels and other liver function tests and to compare the effects between adult and pediatric populations. Methods The process of whole genome imputation of eMERGE samples with standard quality control measures have been described previously. After removing missing data and outliers based on principal components (PC) analyses, 3294 samples from European ancestry were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and total serum bilirubin and other liver function tests was tested using linear regression, adjusting for age, gender, site, platform and ancestry principal components (PC). Results Consistent with previous results, a strong association signal has been detected for UGT1A gene cluster (best SNP rs887829, beta = 0.15, p = 1.30x10-118) for total serum bilirubin level. Indeed, in this region more than 176 SNPs (or indels) had p<10−8 spanning 150Kb on the long arm of chromosome 2q37.1. In addition, we found a similar level of magnitude in a pediatric group (p = 8.26x10-47, beta = 0.17). Further imputation using sequencing data as a reference panel revealed association of other markers including known TA7 repeat indels (rs8175347) (p = 9.78x10-117) and rs111741722 (p = 5.41x10-119) which were in proxy (r2 = 0.99) with rs887829. Among rare variants, two Asian subjects homozygous for coding SNP rs4148323 (G71R) were identified. Additional known effects for total serum bilirubin were also confirmed including organic anion transporters SLCO1B1-SLCO1B3, TDRP and ZMYND8 at FDR<0.05 with no gene-gene interaction effects. Phenome-wide association studies (PheWAS) suggest a protective effect of TA7 repeat against cerebrovascular disease in an adult cohort (OR = 0.75, p = 0.0008). Among other liver function tests, we also confirmed the previous effect of the ABO blood group locus for variation in serum alkaline phosphatase (rs579459, p = 9.44x10-15). Conclusions Taken together, our data present interesting findings with strong confirmation of previous effects by simply using the eMERGE electronic health record phenotyping. In addition, our findings indicate that similar to the adult population, the UGT1A1 is the main locus responsible for normal variation of serum bilirubin in pediatric populations.
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Affiliation(s)
- Bahram Namjou
- Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, OH, United States of America
- University of Cincinnati, College of Medicine, Cincinnati, OH, United States of America
- * E-mail:
| | - Keith Marsolo
- University of Cincinnati, College of Medicine, Cincinnati, OH, United States of America
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America
| | - Todd Lingren
- University of Cincinnati, College of Medicine, Cincinnati, OH, United States of America
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America
| | - Marylyn D. Ritchie
- Center for Systems Genomics, The Pennsylvania State University, University Park, PA, United States of America
| | - Shefali S. Verma
- Center for Systems Genomics, The Pennsylvania State University, University Park, PA, United States of America
| | - Beth L. Cobb
- Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, OH, United States of America
| | - Cassandra Perry
- Division of Genetics and Genomics, Boston Children’s Hospital (BCH), Boston, MA, United States of America
| | - Terrie E. Kitchner
- Center for Human Genetics, Marshfield Clinic, Marshfield, Wisconsin, United States of America
| | - Murray H. Brilliant
- Center for Human Genetics, Marshfield Clinic, Marshfield, Wisconsin, United States of America
| | - Peggy L. Peissig
- Center for Human Genetics, Marshfield Clinic, Marshfield, Wisconsin, United States of America
| | - Kenneth M. Borthwick
- Genomic Medicine Institute, Geisinger Health System, Danville, PA, United States of America
| | - Marc S. Williams
- Genomic Medicine Institute, Geisinger Health System, Danville, PA, United States of America
| | - Jane Grafton
- Group Health Research Institute, Seattle, WA, United States of America
| | - Gail P. Jarvik
- Department of Medicine, University of Washington, Seattle, WA, United States of America
- Department of Genome Sciences, University of Washington, Seattle, WA, United States of America
| | - Ingrid A. Holm
- Division of Genetics and Genomics and The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, United States of America
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States of America
| | - John B. Harley
- Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, OH, United States of America
- University of Cincinnati, College of Medicine, Cincinnati, OH, United States of America
- U.S. Department of Veterans Affairs Medical Center, Cincinnati, OH, United States of America
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Ramírez J, Mirkov S, House LK, Ratain MJ. Glucuronidation of OTS167 in Humans Is Catalyzed by UDP-Glucuronosyltransferases UGT1A1, UGT1A3, UGT1A8, and UGT1A10. Drug Metab Dispos 2015; 43:928-35. [PMID: 25870101 PMCID: PMC4468433 DOI: 10.1124/dmd.115.063271] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 04/13/2015] [Indexed: 01/18/2023] Open
Abstract
OTS167 is a potent maternal embryonic leucine zipper kinase inhibitor undergoing clinical testing as antineoplastic agent. We aimed to identify the UDP-glucuronosyltransferases (UGTs) involved in OTS167 metabolism, study the relationship between UGT genetic polymorphisms and hepatic OTS167 glucuronidation, and investigate the inhibitory potential of OTS167 on UGTs. Formation of a single OTS167-glucuronide (OTS167-G) was observed in pooled human liver (HLM) (Km = 3.4 ± 0.2 µM), intestinal microsomes (HIM) (Km = 1.7 ± 0.1 µM), and UGTs. UGT1A1 (64 µl/min/mg) and UGT1A8 (72 µl/min/mg) exhibited the highest intrinsic clearances (CLint) for OTS167, followed by UGT1A3 (51 µl/min/mg) and UGT1A10 (47 µl/min/mg); UGT1A9 was a minor contributor. OTS167 glucuronidation in HLM was highly correlated with thyroxine glucuronidation (r = 0.91, P < 0.0001), SN-38 glucuronidation (r = 0.79, P < 0.0001), and UGT1A1 mRNA (r = 0.72, P < 0.0001). Nilotinib (UGT1A1 inhibitor) and emodin (UGT1A8 and UGT1A10 inhibitor) exhibited the highest inhibitory effects on OTS167-G formation in HLM (68%) and HIM (47%). We hypothesize that OTS167-G is an N-glucuronide according to mass spectrometry. A significant association was found between rs6706232 and reduced OTS167-G formation (P = 0.03). No or weak UGT inhibition (range: 0-21%) was observed using clinically relevant OTS167 concentrations (0.4-2 µM). We conclude that UGT1A1 and UGT1A3 are the main UGTs responsible for hepatic formation of OTS167-G. Intestinal UGT1A1, UGT1A8, and UGT1A10 may contribute to first-pass OTS167 metabolism after oral administration.
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Affiliation(s)
| | - Snezana Mirkov
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Larry K House
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Mark J Ratain
- Department of Medicine, University of Chicago, Chicago, Illinois
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Lu L, Zhou J, Shi J, Peng XJ, Qi XX, Wang Y, Li FY, Zhou FY, Liu L, Liu ZQ. Drug-Metabolizing Activity, Protein and Gene Expression of UDP-Glucuronosyltransferases Are Significantly Altered in Hepatocellular Carcinoma Patients. PLoS One 2015; 10:e0127524. [PMID: 26010150 PMCID: PMC4444081 DOI: 10.1371/journal.pone.0127524] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 04/16/2015] [Indexed: 02/07/2023] Open
Abstract
UDP-glucuronosyltransferases (UGTs), the most important enzymes in body detoxification and homeostasis maintaining, govern the glucuronidation reaction of various endogenous and environmental carcinogens. The metabolic function of UGTs can be severely influenced by hepatocellular carcinoma (HCC), the fifth prevalent and third malignant cancer worldwide. Particularly in China, HBV-positive HCC account for approximately 80% of HCC patients. But rare papers addressed the alteration on the metabolism of UGTs specific substrates, translational and transcriptional activity of UGTs in HBV-positive HCC patients. In present study, we choose the main UGT isoforms, UGT1As, UGT1A1, UGT1A9, UGT1A4 and UGT2B7, to determine the alterations of metabolic activity, protein and gene expression of UGTs in HBV-positive HCC. The corresponding specific substrates such as genistein, SN-38, tamoxifen, propofol and zidovudine were utilized respectively in UGTs metabolic activity determination. Furthermore, the plausible mechanism responsible for UGTs alterations was addressed by analyzing the protein and gene expressions in tumor and the adjacent normal tissues in HBV-positive HCC. The results revealed that in the tumor human liver microsomes (HLMs), either V(max) (maximum reaction rate, R(max) for UGT1A1) or the clearance rates (V(max)/K(m), Clint) of UGT1A, UGT1A1, UGT1A4, UGT1A9 and UGT2B7 were significant lower than those of in the adjacent normal HLMs. Subsequently, the relative protein and gene expressions of these isoforms were notably decreased in most of tumor tissues comparing with the adjacent normal tissues. More interestingly, in tumor tissues, the metabolic activity reduction ratio of each UGT isoform was closely related to its protein reduction ratio, indicating that decreasing protein level would contribute to the reduced metabolic function of UGTs in HBV-positive HCC. In summary, our study firstly determined the alteration of UGT function in HBV-positive HCC patients, which would provide an important insight for toxicity or efficacy determination of chemotherapeutic drugs, and even bring a new strategy for clinical regimen in the health cares for the relative patients.
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Affiliation(s)
- Linlin Lu
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China
| | - Juan Zhou
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, PR China
| | - Jian Shi
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, PR China
| | - Xiao-juan Peng
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, PR China
| | - Xiao-xiao Qi
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China
| | - Ying Wang
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, PR China
| | - Fang-yuan Li
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China
| | - Fu-Yuan Zhou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Liang Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (SAR), 999078, PR China
| | - Zhong-Qiu Liu
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, PR China
- * E-mail:
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Li L, Deng G, Tang Y, Mao Q. Spectrum of UGT1A1 Variations in Chinese Patients with Crigler-Najjar Syndrome Type II. PLoS One 2015; 10:e0126263. [PMID: 25993113 PMCID: PMC4439166 DOI: 10.1371/journal.pone.0126263] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Accepted: 03/23/2015] [Indexed: 01/24/2023] Open
Abstract
Crigler–Najjar Syndrome type II (CNS-II) is an autosomal recessive hereditary condition of unconjugated hyperbilirubinemia without hemolysis, with bilirubin levels ranging from 102.6 μmol/L to 342 μmol/L. CNS-II is caused by a deficiency of UDP-glucuronyl transferase (UGT), which is encoded by the UDP-glucuronyl transferase 1A1 gene (UGT1A1). In East Asian populations, the compound homozygous UGT1A1 G71R and Y486D variants are frequently observed in cases with bilirubin levels exceeding 200 μmol/L. In this study, we investigated the spectrum of UGT1A1 variations in Chinese CNS-II patients. We sequenced the enhancer, promoter, and coding regions of UGT1A1 in 11 unrelated Chinese CNS-II patients and 80 healthy controls. Nine of these patients carried variations that are here reported for the first time in CNS-II patients, although they have been previously reported for other types of hereditary unconjugated hyperbilirubinemia. These individual variations have less influence on UGT activity than do the compound homozygous variation (combination of homozygous G71R variant and Y486D variant). Therefore, we propose that the spectrum of UGT1A1 variations in CNS-II differs according to the bilirubin levels.
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Affiliation(s)
- Lufeng Li
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Guohong Deng
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
- The Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China
| | - Yi Tang
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Qing Mao
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
- The Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China
- * E-mail:
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Wang H, Bian T, Jin T, Chen Y, Lin A, Chen C. Association analysis of UGT1A genotype and haplotype with SN-38 glucuronidation in human livers. Pharmacogenomics 2014; 15:785-98. [PMID: 24897286 DOI: 10.2217/pgs.14.29] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan, is mainly eliminated hepatically through glucuronidation by UGT1A1 and UGT1A9 enzymes. This study comprehensively investigates the effects of UGT1A1 and UGT1A9 genetic polymorphism on SN-38 glucuronidation activity. MATERIALS & METHODS Genetic polymorphisms and combinational haplotypes of UGT1A1 and UGT1A9, SN-38 glucuronidation activities, and protein levels of UGT1A1 and UGT1A9 were determined using a set of over 45 Chinese livers. RESULTS UGT1A1 reduced function variants UGT1A1*6, *28, *60 and *1B exhibited additive effect. The number of UGT1A1 reduced function alleles was associated with decreased SN-38G formation rates and UGT1A protein levels. UGT1A9 I399C>T and UGT1A9*1b, which were highly linked, were associated with increased SN-38 glucuronidation activity and UGT1A protein levels. However, further analysis based on UGT1A9-1A1 haplotypes confirmed that their increased effect was partly due to their close linkage with UGT1A1 reduced function alleles. CONCLUSION UGT1A1 genetic polymorphisms have a more important function in human liver SN-38 glucuronidation activity than UGT1A9. Original submitted 7 November 2013; Revision submitted 30 January 2014.
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Affiliation(s)
- Huijuan Wang
- National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, 229 North Taibai Road, Xi'an 710069, China.
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Associations between UGT1A1*6 or UGT1A1*6/*28 polymorphisms and irinotecan-induced neutropenia in Asian cancer patients. Cancer Chemother Pharmacol 2014; 73:779-88. [PMID: 24519753 DOI: 10.1007/s00280-014-2405-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Accepted: 01/28/2014] [Indexed: 01/21/2023]
Abstract
PURPOSE Neutropenia is a life-threatening side effect of irinotecan, and uridine diphosphate glucuronosyltransferases (UGTs) gene polymorphisms are considered to be one of the predictive markers of irinotecan-related toxicities. Many studies have demonstrated that patients bearing UGT1A1*28 have a higher risk of severe neutropenia on toxicity of irinotecan. However, UGT1A1 (TA7/TA7) was very rare in Asian populations. Some researches reported that UGT1A1*28 and/or UGT1A1*6 could predict irinotecan-induced toxicities in Asian populations, but controversial conclusions still remained. This study aims to investigate the association between UGT1A1 gene polymorphisms *6, *6/*28 and irinotecan-related neutropenia in Asian cancer patients receiving irinotecan regimen chemotherapy. EXPERIMENTAL DESIGN Meta-analyses were done to assess the relationship between UGT1A1*6 or UGT1A1*6/*28 and irinotecan-induced neutropenia. RESULTS The risk of neutropenia was significantly higher among patients with a UGT1A1*6 genotype than among those carrying the UGT1A1*1 allele(s) [odds ratio (OR) 3.276; 95 % confidence interval (CI) 1.887-5.688; P = 0.000 (*6/*6 vs. *1/*6 or *1/*1)], [OR 1.542; 95 % CI 1.180-2.041; P = 0.001 (*6/*6 or *1/*6 vs. *1/*1)]. Also, the risk was significantly higher among patients with a UGT1A1*6/*28 than among those carrying the UGT1A1*1 allele(s) [OR 3.275; 95 % CI 2.152-4.983; P = 0.000 (*6/*6 or *28/*28 or *6/*28 vs. *1/*6 or *1/*28 or *1/*1)]. CONCLUSIONS In conclusion, the UGT1A1*6 and UGT1A1*6/*28 genotypes were associated with an increased risk of irinotecan-induced neutropenia in Asian cancer patients.
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Ishii Y, Koba H, Kinoshita K, Oizaki T, Iwamoto Y, Takeda S, Miyauchi Y, Nishimura Y, Egoshi N, Taura F, Morimoto S, Ikushiro S, Nagata K, Yamazoe Y, Mackenzie PI, Yamada H. Alteration of the function of the UDP-glucuronosyltransferase 1A subfamily by cytochrome P450 3A4: different susceptibility for UGT isoforms and UGT1A1/7 variants. Drug Metab Dispos 2014; 42:229-38. [PMID: 24255116 DOI: 10.1124/dmd.113.054833] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
Functional protein-protein interactions between UDP-glucuronosyltransferase (UGT)1A isoforms and cytochrome P450 (CYP)3A4 were studied. To this end, UGT1A-catalyzed glucuronidation was assayed in Sf-9 cells that simultaneously expressed UGT and CYP3A4. In the kinetics of UGT1A6-catalyzed glucuronidation of serotonin, both Michaelis constant (Km) and maximal velocity (Vmax) were increased by CYP3A4. When CYP3A4 was coexpressed with either UGT1A1 or 1A7, the Vmax for the glucuronidation of the irinotecan metabolite (SN-38) was significantly increased. S50 and Km both which are the substrate concentration giving 0.5 Vmax were little affected by simultaneous expression of CYP3A4. This study also examined the catalytic properties of the allelic variants of UGT1A1 and 1A7 and their effects on the interaction with CYP3A4. Although the UGT1A1-catalyzing activity of 4-methylumbelliferone glucuronidation was reduced in its variant, UGT1A1*6, the coexpression of CYP3A4 restored the impaired function to a level comparable with the wild type. Similarly, simultaneous expression of CYP3A4 increased the Vmax of UGT1A7*1 (wild type) and *2 (N129K and R131K), whereas the same was not observed in UGT1A7*3 (N129K, R131K, and W208R). In the kinetics involving different concentrations of UDP-glucuronic acid (UDP-GlcUA), the Km for UDP-GlcUA was significantly higher for UGT1A7*2 and *3 than *1. The Km of UGT1A7*1 and *3 was increased by CYP3A4, whereas *2 did not exhibit any such change. These results suggest that (1) CYP3A4 changes the catalytic function of the UGT1A subfamily in a UGT isoform-specific manner and (2) nonsynonymous mutations in UGT1A7*3 reduce not only the ability of UGT to use UDP-GlcUA but also CYP3A4-mediated enhancement of catalytic activity, whereas CYP3A4 is able to restore the UGT1A1*6 function.
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Affiliation(s)
- Yuji Ishii
- Laboratory of Molecular Life Sciences (Y.Is., H.K., K.K., T.O., Y.Iw., S.T., Y.M., Y.N., N.E., H.Y.) and Laboratory of Medicinal Resource Regulation (F.T., S.M.), Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; Biotechnology Research Center, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama, Japan (S.I.); Tohoku Pharmaceutical University, Sendai, Japan (K.N.); Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (Y.Y.); and Department of Clinical Pharmacology, Flinders Medical Centre and Flinders University, Adelaide, Australia (P.I.M.)
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Cheng L, Li M, Hu J, Ren W, Xie L, Sun ZP, Liu BR, Xu GX, Dong XL, Qian XP. UGT1A1*6 polymorphisms are correlated with irinotecan-induced toxicity: a system review and meta-analysis in Asians. Cancer Chemother Pharmacol 2014; 73:551-60. [PMID: 24448639 DOI: 10.1007/s00280-014-2382-3] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2013] [Accepted: 01/08/2014] [Indexed: 12/14/2022]
Abstract
PURPOSE Previous studies confirmed that genotyping uridine diphosphate glucuronosyltransferase (UGT) 1A1*28 polymorphisms could predict the side effects in cancer patients using irinotecan (IRI) and then reduce IRI-induced toxicity by preventative treatment or decrease in dose. However, the association between UGT1A1*6 polymorphisms and IRI-induced severe toxicity in Asian patients is still unclear. The aim of this study was to evaluate the association between UGT1A1*6 polymorphisms and IRI-induced severe neutropenia as well as diarrhea in Asian patients. METHODS We searched all papers on PubMed and Embase from February 1998 to August 2013. Then we assessed the methodologies quality, extracted data and made statistics analysis using STATA software. To uncover the sources of heterogeneity, subgroup meta-analysis was conducted according to the dosage of IRI. RESULTS Eleven papers were included according to the inclusion and exclusion criteria after searching Pubmed and Embase. Overall, an increased risk of severe toxicity in Asian patients with UGT1A1*6 polymorphisms was found. Patients with heterozygous variant of UGT1A1*6 showed an increased risk [odds ratio (OR) = 1.98, 95 % confidence intervals (CI) 1.45-2.71, P < 0.001], and homozygous mutation showed an even higher risk (OR = 4.44, 95 % CI 2.42-8.14, P < 0.001) for severe neutropenia. For severe diarrhea, heterozygous variant of UGT1A1*6 showed no significant risk, while the homozygous variant performed a notable risk (OR = 3.51, 95 % CI 1.41-8.73, P = 0.007). Subgroup meta-analysis indicated that for patients harboring either heterozygous or homozygous variant, low dose of IRI also presented comparably increased risk in suffering severe neutropenia. CONCLUSION In this meta-analysis, UGT1A1*6 polymorphisms were revealed as potential biomarkers, predicting IRI-induced severe toxicity in patients from Asia, and increased incidences of severe neutropenia could occur in both high/medium and low doses of IRI.
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Affiliation(s)
- Lei Cheng
- Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, 210008, China,
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Prijovich ZM, Burnouf PA, Roffler SR. Versatile online SPE-HPLC method for the analysis of Irinotecan and its clinically relevant metabolites in biomaterials. J Sep Sci 2014; 37:360-7. [DOI: 10.1002/jssc.201301191] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 12/05/2013] [Accepted: 12/05/2013] [Indexed: 11/09/2022]
Affiliation(s)
- Zeljko M. Prijovich
- Institute of Biomedical Sciences; Academia Sinica; Taipei Taiwan
- Faculty of Medicine; University of Patras; Rio Greece
| | | | - Steve R. Roffler
- Institute of Biomedical Sciences; Academia Sinica; Taipei Taiwan
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Kim JY, Cheong HS, Park BL, Kim LH, Namgoong S, Kim JO, Kim HD, Kim YH, Chung MW, Han SY, Shin HD. Comprehensive variant screening of the UGT gene family. Yonsei Med J 2014; 55:232-9. [PMID: 24339312 PMCID: PMC3874916 DOI: 10.3349/ymj.2014.55.1.232] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE UGT1A1, UGT2B7, and UGT2B15 are well-known pharmacogenes that belong to the uridine diphosphate glucuronyltransferase gene family. For personalized drug treatment, it is important to study differences in the frequency of core markers across various ethnic groups. Accordingly, we screened single nucleotide polymorphisms (SNPs) of these three genes and analyzed differences in their frequency among five ethnic groups, as well as attempted to predict the function of novel SNPs. MATERIALS AND METHODS We directly sequenced 288 subjects consisting of 96 Korean, 48 Japanese, 48 Han Chinese, 48 African American, and 48 European American subjects. Subsequently, we analyzed genetic variability, linkage disequilibrium (LD) structures and ethnic differences for each gene. We also conducted in silico analysis to predict the function of novel SNPs. RESULTS A total of 87 SNPs were detected, with seven pharmacogenetic core SNPs and 31 novel SNPs. We observed that the frequencies of UGT1A1 *6 (rs4148323), UGT1A1 *60 (rs4124874), UGT1A1 *93 (rs10929302), UGT2B7 *2 (rs7439366), a part of UGT2B7 *3 (rs12233719), and UGT2B15 *2 (rs1902023) were different between Asian and other ethnic groups. Additional in silico analysis results showed that two novel promoter SNPs of UGT1A1 -690G>A and -689A>C were found to potentially change transcription factor binding sites. Moreover, 673G>A (UGT2B7), 2552T>C, and 23269C>T (both SNPs from UGT2B15) changed amino acid properties, which could cause structural deformation. CONCLUSION Findings from the present study would be valuable for further studies on pharmacogenetic studies of personalized medicine and drug response.
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Affiliation(s)
- Jason Yongha Kim
- Department of Life Science, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 121-742, Korea.
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Hirasawa A, Zama T, Akahane T, Nomura H, Kataoka F, Saito K, Okubo K, Tominaga E, Makita K, Susumu N, Kosaki K, Tanigawara Y, Aoki D. Polymorphisms in the UGT1A1 gene predict adverse effects of irinotecan in the treatment of gynecologic cancer in Japanese patients. J Hum Genet 2013; 58:794-8. [PMID: 24088669 DOI: 10.1038/jhg.2013.105] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2013] [Revised: 08/16/2013] [Accepted: 09/09/2013] [Indexed: 12/22/2022]
Abstract
Irinotecan is a key chemotherapeutic drug used to treat many tumors, including cervical and ovarian cancers; however, irinotecan can cause toxicity, particularly in the presence of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms, which are associated with reduced enzyme activity. Here, we investigated the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28) and their relationships with irinotecan-induced adverse events in patients with gynecologic cancer, who are treated with lower doses of irinotecan than patients with other types of solid tumors. Fifty-three female patients treated with irinotecan and 362 female patients not treated with irinotecan were screened for UGT1A1*6, UGT1A1*27 and UGT1A1*28. Homozygosity for UGT1A1*6 or heterozygosity for UGT1A1*6/*28 was associated with a high risk of severe absolute neutrophil count decrease or diarrhea (odds ratios: 16.03 and 31.33, respectively). In contrast, serum bilirubin levels were not associated with irinotecan toxicity. Homozygosity for UGT1A1*6/*6 and heterozygosity for UGT1A1*6/*28 were associated with an increased risk of absolute neutrophil count and/or diarrhea in Japanese gynecologic cancer patients, despite the lower doses of irinotecan used in these patients. UGT1A1*6 and UGT1A1*28 are potential predictors of severe absolute neutrophil decrease and diarrhea caused by low-dose irinotecan in gynecologic cancer patients.
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Affiliation(s)
- Akira Hirasawa
- 1] Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan [2] Center for Medical Genetics, School of Medicine, Keio University, Tokyo, Japan
| | - Takeru Zama
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Tomoko Akahane
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan
| | - Hiroyuki Nomura
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan
| | - Fumio Kataoka
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan
| | - Koichiro Saito
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Keisuke Okubo
- Department of Otolaryngology, Sano Kosei General Hospital, Tochigi, Japan
| | - Eiichiro Tominaga
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan
| | - Kazuya Makita
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan
| | - Nobuyuki Susumu
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan
| | - Kenjiro Kosaki
- Center for Medical Genetics, School of Medicine, Keio University, Tokyo, Japan
| | - Yusuke Tanigawara
- Department of Clinical Pharmacokinetics and Pharmacodynamics, School of Medicine, Keio University, Tokyo, Japan
| | - Daisuke Aoki
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan
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Alkharfy KM, Alghamdi AM, Bagulb KM, Al-Jenoobi FI, Al-Mohizea AM, Al-Muhsen S, Halwani R, Parvez MK, Al-Dosari MS. Distribution of selected gene polymorphisms of UGT1A1 in a Saudi population. Arch Med Sci 2013; 9:731-738. [PMID: 24049537 PMCID: PMC3776187 DOI: 10.5114/aoms.2013.37012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Revised: 04/26/2012] [Accepted: 07/16/2012] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION Glucuronidation is an important phase II pathway responsible for the metabolism of many endogenous substances and drugs to less toxic metabolites, which undergo renal excretion. The aim of the current work was to evaluate genotype and allele frequencies of certain UDP-glucuronosyltransferase 1A1 (UGT1A1) variants in an Arab population. MATERIAL AND METHODS Genomic DNA was isolated from 192 healthy unrelated Saudi males of various geographic regions and genotyping of UGT1A1*6, *27, *36, *28, *37, and *60 was carried out using polymerase chain reaction (PCR) amplification followed by direct sequencing. RESULTS The most common allele for (TA) repeats was the wild type (TA)6 with a frequency of 74.3% followed by the mutant (TA)7 (i.e., UGT1A1*28) with a frequency of 25.7%. The distribution of UGT1A1*60 allele was 62.4% among subjects with the homozygous mutant genotype of 35.4%, while the wild type variant represents 10.6% only. Both UGT1A1*6 and *27 were not detected as all screened subjects showed a homozygous wild type pattern. Similarly, UGT1A1*36* and *37 were either not present or rarely found, respectively. In comparison to other populations, the frequency of UGT1A1*60 and *28 in the studied population was less than that of African Americans but higher than Asians. The geographical origin of the study subjects also implied some differences in genotype distribution of (TA) repeats and UGT1A1*60. CONCLUSIONS Our data indicate that Saudis harbor some important UGT1A1 mutations known to affect enzyme activity. Additional studies are warranted to assess the clinical implications of these gene polymorphisms in this ethnic group.
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Affiliation(s)
- Khalid M. Alkharfy
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
- Biomarkers Research Program, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Amal M. Alghamdi
- Department of Pediatrics, Asthma Research Chair and Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Khawla M. Bagulb
- Department of Pediatrics, Asthma Research Chair and Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Fahad I. Al-Jenoobi
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Abdullah M. Al-Mohizea
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Saleh Al-Muhsen
- Department of Pediatrics, Asthma Research Chair and Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Rabih Halwani
- Department of Pediatrics, Asthma Research Chair and Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mohammad K. Parvez
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed S. Al-Dosari
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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Kobayashi M, Hazama S, Takahashi K, Oba K, Okayama N, Nishioka M, Hinoda Y, Oka M, Okamoto K, Maeda H, Nakamura D, Sakamoto J, Mishima H. Is there diversity among UGT1A1 polymorphism in Japan. World J Gastrointest Oncol 2012; 4:170-5. [PMID: 22848786 PMCID: PMC3406281 DOI: 10.4251/wjgo.v4.i7.170] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Revised: 05/22/2012] [Accepted: 05/27/2012] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate into the diversity of UGT1A1 polymorphism across three different districts in Japan and highlight genetic differences among the population in Japan.
METHODS: We enrolled 50 healthy volunteers from each of the Yamaguchi (western part of Japan), Kochi (southern part of Japan) and Akita (northern part of Japan) prefectures. Blood samples (7 mL) were collected from each participant and stored in EDTA for subsequent genotyping by fragment size analysis, direct sequencing and TaqMan assay of UGT1A1*28, UGT1A7*3/UGT1A9*22 and UGT1A1*93/UGT1A1*6/UGT1A1*27/UGT1A1*60/UGT1A7 (-57), respectively.
RESULTS: The only statistically significant differences in allele polymorphisms among the group examined were for UGT1A1*6. The Akita population showed more UGT1A1*6 heterozygosity (P = 0.0496).
CONCLUSION: Our study revealed no regional diversity among UGT1A1, UGT1A7 or UGT1A9 polymorphisms in Japan.
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Affiliation(s)
- Michiya Kobayashi
- Michiya Kobayashi, Ken Okamoto, Hiromichi Maeda, Department of Human Health and Medical Sciences, Kochi Medical School, Nankoku 783-8505, Japan
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Peer CJ, Sissung TM, Kim A, Jain L, Woo S, Gardner ER, Kirkland CT, Troutman SM, English BC, Richardson ED, Federspiel J, Venzon D, Dahut W, Kohn E, Kummar S, Yarchoan R, Giaccone G, Widemann B, Figg WD. Sorafenib is an inhibitor of UGT1A1 but is metabolized by UGT1A9: implications of genetic variants on pharmacokinetics and hyperbilirubinemia. Clin Cancer Res 2012; 18:2099-107. [PMID: 22307138 PMCID: PMC6432766 DOI: 10.1158/1078-0432.ccr-11-2484] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)(5/6/7) repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration. EXPERIMENTAL DESIGN Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype. RESULTS Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC(50) = 18 μmol/L; K(i) = 11.7 μmol/L) in vitro. Five patients carrying UGT1A1*28/*28 (n = 4) or UGT1A9*3/*3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n = 12 and n = 5; R(2) = 0.38 and R(2) = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure. CONCLUSIONS This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib.
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Affiliation(s)
- Cody J. Peer
- Clinical Pharmacology Program, National Cancer Institute, Bethesda, MD
| | | | - AeRang Kim
- Pharmacology and Experimental Therapeutics Section, National Cancer Institute, Bethesda, MD
| | - Lokesh Jain
- Clinical Pharmacology Program, National Cancer Institute, Bethesda, MD
| | - Sukyung Woo
- Clinical Pharmacology Program, National Cancer Institute, Bethesda, MD
| | - Erin R. Gardner
- Clinical Pharmacology Program, National Cancer Institute, Bethesda, MD
| | - C. Tyler Kirkland
- Molecular Pharmacology Section, National Cancer Institute, Bethesda, MD
| | - Sarah M. Troutman
- Molecular Pharmacology Section, National Cancer Institute, Bethesda, MD
| | - Bevin C. English
- Molecular Pharmacology Section, National Cancer Institute, Bethesda, MD
| | | | - Joel Federspiel
- Clinical Pharmacology Program, National Cancer Institute, Bethesda, MD
| | - David Venzon
- Biostatistics and Data Management Branch, National Cancer Institute, Bethesda, MD
| | - William Dahut
- Medical Oncology Branch, National Cancer Institute, Bethesda, MD
| | - Elise Kohn
- Medical Oncology Branch, National Cancer Institute, Bethesda, MD
| | - Shivaani Kummar
- Medical Oncology Branch, National Cancer Institute, Bethesda, MD
| | - Robert Yarchoan
- HIV/AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD
| | | | - Brigitte Widemann
- Pharmacology and Experimental Therapeutics Section, National Cancer Institute, Bethesda, MD
| | - William D. Figg
- Clinical Pharmacology Program, National Cancer Institute, Bethesda, MD
- Molecular Pharmacology Section, National Cancer Institute, Bethesda, MD
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Kurose K, Sugiyama E, Saito Y. Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. Drug Metab Pharmacokinet 2011; 27:9-54. [PMID: 22123129 DOI: 10.2133/dmpk.dmpk-11-rv-111] [Citation(s) in RCA: 184] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Drug lag, recently discussed extensively in Japan, can be divided into two phases: clinical development time and application review time. The former factor is still an important problem that might be improved by promoting multi-regional clinical trials and considering the results from other similar populations with Japanese, such as Koreans and Chinese. In this review, we compare the allelic or genotype frequencies of 30 relatively common functional alleles mainly between Eastern Asians and Europeans as well as among 3 major populations in Eastern Asian countries, Japan, Korea, and China, in 12 pharmacokinetics (PK)/pharmacodynamics (PD)-related genes; CYP2C9 (*2 and *3), CYP2C19 (*2, *3 and *17), 13 CYP2D6 haplotypes including *4, *5 and *10, CYP3A5 (*3), UGT1A1 (*28 and *6), NAT2 (*5, *6 and *7), GSTM1 and GSTT1 null genotypes, SLCO1B1 521T>C, ABCG2 421C>A, and HLA-A*31:01 and HLA-B*58:01. In this review, differences in allele frequencies (AFs) or genotype frequencies (GFs) less than 0.1 (in the cases of highest AF (GF) ≥0.1) or less than 0.05 (in the cases of lowest AF (GF) <0.1) were regarded as similar. Between Eastern Asians and Europeans, AFs (or GFs) are regarded as being different for many alleles such as CYP2C9 (*2), CYP2C19 (*2, *3 and *17), CYP2D6 (*4 and *10), CYP3A5 (*3), UGT1A1 (*28 and *6), NAT2 (*5*7), GSTT1 null and ABCG2 421C>A. Among the 3 Eastern Asian populations, however, only AFs of CYP2C19*3, CYP2D6*10, HLA-A*31:01 and HLA-B*58:01 are regarded as dissimilar. For CYP2C19*3, the total functional impact on CYP2C19 could be small if the frequencies of the two null alleles CYP2C19*2 and *3 are combined. Regarding CYP2D6*10, frequency difference over 0.1 is observed only between Japanese and Chinese (0.147). Although environmental factors should be considered for PK/PD differences, we could propose that among Japan, Korea, and China, genetic differences are very small for the analyzed common PK-related gene polymorphisms. On the other hand, AFs of the two HLA alleles important for cutaneous adverse drug reactions are diverse even among Eastern Asians and thus should be taken into account.
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Affiliation(s)
- Kouichi Kurose
- Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan
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Kalotychou V, Karakosta M, Tzanetea R, Stamoulakatou A, Konstantopoulos K, Rombos Y. Contribution of G71R mutation to Gilbert’s syndrome phenotype in a Greek patient: A case report. World J Gastrointest Pharmacol Ther 2011; 2:42-5. [PMID: 22046580 PMCID: PMC3205121 DOI: 10.4292/wjgpt.v2.i5.42] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Revised: 09/20/2011] [Accepted: 09/28/2011] [Indexed: 02/06/2023] Open
Abstract
Gilbert’s syndrome is characterized by a benign indirect hyperbilirubinemia. It has often been underestimated and undiagnosed because of its mild symptoms; although it is not as rare as was once believed when its frequency was estimated using data originating from biochemical tests. Based on molecular techniques, the occurrence of Gilbert’s syndrome has changed, increasing to 10% in the Caucasian population. This molecular defect was described, by Bosma et al, in 1995, and affects the promoter region of the UGT 1A1 gene. In this case report, our aim is to present a new combination of two molecular defects in a Greek patient with Gilbert’s syndrome. A 13-year-old Greek girl was examined for Gilbert’s syndrome using molecular techniques, and an uncommon genotype was revealed comprising the rare mutation G71R in trans with A(TA)7TAA motif. The G71R mutation according to the literature, as well as our epidemiological data, is rare in Caucasians, while it is common in Asian populations. This is the first case study in the Greek population to report a new genotype for Gilbert’s syndrome manifestation in the Caucasian population.
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Affiliation(s)
- Vassiliki Kalotychou
- Vassiliki Kalotychou, Maria Karakosta, Revekka Tzanetea, Kostas Konstantopoulos, Yannis Rombos, 1st Department of Internal Medicine, University of Athens, Athens, 11527, Greece
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Sai K, Saito Y. Ethnic differences in the metabolism, toxicology and efficacy of three anticancer drugs. Expert Opin Drug Metab Toxicol 2011; 7:967-88. [PMID: 21585235 DOI: 10.1517/17425255.2011.585969] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Large inter-individual and inter-ethnic differences are observed in efficacies and toxicities of medical drugs. To improve the predictability of these differences, pharmacogenetic information has been applied to clinical situations. Expanding pharmacogenetic information would be a valuable tool to the medical community as well as the patient to fulfill the promise of personalized anticancer drug therapy. AREAS COVERED This review highlights genetic polymorphisms and ethnic differences of genes, UGT1As, CYP3A4, CES1As, ABCB1, ABCC2, ABCG2, SLCO1B1, CDA and CYP2D6, involved in metabolism and disposition of three anticancer drugs: irinotecan, gemcitabine and tamoxifen. EXPERT OPINION Recent pharmacogenetic studies have successfully identified distinct ethnic differences in genetic polymorphisms that are potentially involved in efficacies and toxicities of anticancer drugs. This achievement has led to personalized irinotecan therapy, reflecting ethnic differences in UGT1A1 genotypes, and possible benefits of genetic testing have also been suggested for gemcitabine and tamoxifen therapy, which still requires further validation. The ultimate goal for patients is a high rate or even perfect prediction of efficacies and toxicities of anticancer drugs in each ethnic population. For this challenge, more clinical studies combined with comprehensive omics approaches are necessary to further advance the field.
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Affiliation(s)
- Kimie Sai
- National Institute of Health Sciences , Division of Medicinal Safety Science, Kamiyoga, Setagaya-ku, Tokyo, Japan
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Bellanti F, Kågedal B, Della Pasqua O. Do pharmacokinetic polymorphisms explain treatment failure in high-risk patients with neuroblastoma? Eur J Clin Pharmacol 2011; 67 Suppl 1:87-107. [PMID: 21287160 PMCID: PMC3112027 DOI: 10.1007/s00228-010-0966-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2010] [Accepted: 11/27/2010] [Indexed: 12/30/2022]
Abstract
PURPOSE Neuroblastoma is the most common extracranial solid tumour in childhood. It accounts for 15% of all paediatric oncology deaths. In the last few decades, improvement in treatment outcome for high-risk patients has not occurred, with an overall survival rate <30-40%. Many reasons may account for such a low survival rate. The aim of this review is to evaluate whether pharmacogenetic factors can explain treatment failure in neuroblastoma. METHODS A literature search based on PubMed's database Medical Subject Headings (MeSH) was performed to retrieve all pertinent publications on current treatment options and new classes of drugs under investigation. One hundred and fifty-eight articles wer reviewed, and relevant data were extracted and summarised. RESULTS AND CONCLUSIONS Few of the large number of polymorphisms identified thus far showed an effect on pharmacokinetics that could be considered clinically relevant. Despite their clinical relevance, none of the single nucleotide polymorphisms (SNPs) investigated can explain treatment failure. These findings seem to reflect the clinical context in which anti-tumour drugs are used, i.e. in combination with multimodal therapy. In addition, many pharmacogenetic studies did not assess (differences in) drug exposure, which could contribute to explaining pharmacogenetic associations. Furthermore, it remains unclear whether the significant activity of new drugs on different neuroblastoma cell lines translates into clinical efficacy, irrespective of resistance or myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN) amplification. Elucidation of the clinical role of pharmacogenetic factors in the treatment of neuroblastoma demands an integrated pharmacokinetic-pharmacodynamic approach to the analysis of treatment response data.
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Affiliation(s)
- Francesco Bellanti
- Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands
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Hanioka N, Tanabe N, Jinno H, Tanaka-Kagawa T, Nagaoka K, Naito S, Koeda A, Narimatsu S. Functional characterization of human and cynomolgus monkey UDP-glucuronosyltransferase 1A1 enzymes. Life Sci 2010; 87:261-8. [DOI: 10.1016/j.lfs.2010.07.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2010] [Revised: 06/24/2010] [Accepted: 06/30/2010] [Indexed: 10/19/2022]
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Kang TW, Kim HJ, Ju H, Kim JH, Jeon YJ, Lee HC, Kim KK, Kim JW, Lee S, Kim JY, Kim SY, Kim YS. Genome-wide association of serum bilirubin levels in Korean population. Hum Mol Genet 2010; 19:3672-8. [PMID: 20639394 DOI: 10.1093/hmg/ddq281] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
A large-scale, genome-wide association study was performed to identify genetic variations influencing serum bilirubin levels using 8841 Korean individuals. Significant associations were observed at UGT1A1 (rs11891311, P = 4.78 x 10(-148)) and SLCO1B3 (rs2417940, P = 1.03 x 10(-17)), which are two previously identified loci. The two single-nucleotide polymorphisms (SNPs) were replicated (rs11891311, P = 3.18 x 10(-15)) or marginally significant (rs2417940, P = 8.56 x 10(-4)) in an independent cohort of 1096 individuals. In a conditional analysis adjusted for the top UGT1A1 variant (rs11891311), another variant in UGT1A1 (rs4148323, P = 1.22 x 10(-121)) remained significant; this suggests that in UGT1A1 at least two independent genetic variations influence the bilirubin levels in the Korean population. The protein coding variant rs4148323, which is monomorphic in European-derived populations, may be specifically associated with serum bilirubin levels in Asians (P = 2.56 x 10(-70)). The SLCO1B3 variant (rs2417940, P = 1.67 x 10(-18)) remained significant in a conditional analysis for the top UGT1A1 variant. Interestingly, there were significant differences in the associated variations of SLCO1B3 between Koreans and European-derived populations. While the variant rs2417940 at intron 7 of SLCO1B3 was more significantly associated in Koreans, variants rs17680137 (P = 0.584) and rs2117032 (P = 2.76 x 10(-5)), two of the top-ranked SNPs in European-derived populations, did not reach the genome-wide significance level. Also, variants in SLCO1B1 did not reach genome-wide significance in Koreans. Our result supports the idea that there are considerable ethnic differences in genetic association of bilirubin levels between Koreans and European-derived populations.
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Affiliation(s)
- Tae-Wook Kang
- Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea
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Kisaki O, Kato S, Shinohara K, Hiura H, Samori T, Sato H. High-throughput single-base mismatch detection for genotyping of UDP-glucuronosyltransferase (UGT1A1) with probe capture assay coupled with modified allele-specific primer extension reaction (MASPER). J Clin Lab Anal 2010; 24:85-91. [PMID: 20333765 DOI: 10.1002/jcla.20359] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
We have developed a new method based on specific primer extension reactions coupled with plate hybridization for high-throughput genotyping of single-base mutations. To improve the switching characteristics of the primer extension reaction, we introduced an artificial mismatch two bases upstream of the 3'-terminal base in the detection primers. A set of primers that correspond to wild-type and mutant DNA segments can be used to accurately analyze single-base mutations. The termini of these primers are at the mutation positions. The primer extension products produced by polymerase chain reaction (PCR) were captured by an oligonucleotide probe immobilized on the surface of microtiter wells and were detected by a colorimetric assay using the streptavidin-conjugated horseradish peroxidase. We used the new method to genotype 96 individuals for 211G>A (G71R) and 119 for 1456T>G (Y486D) in the UDP-glucuronosyltransferase1A1 gene; the results were completely concordant with those found by direct sequencing. The proposed method includes ordinary PCR and a microplate assay format, and may be used in routine laboratory tests.
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Affiliation(s)
- Osamu Kisaki
- Japan Clinical Laboratories, Kumiyama, Kuze-gun, Kyoto, Japan
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