|
1
|
Smirne C, Croce E, Di Benedetto D, Cantaluppi V, Comi C, Sainaghi PP, Minisini R, Grossini E, Pirisi M. Oxidative Stress in Non-Alcoholic Fatty Liver Disease. LIVERS 2022; 2:30-76. [DOI: 10.3390/livers2010003] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a challenging disease caused by multiple factors, which may partly explain why it still remains an orphan of adequate therapies. This review highlights the interaction between oxidative stress (OS) and disturbed lipid metabolism. Several reactive oxygen species generators, including those produced in the gastrointestinal tract, contribute to the lipotoxic hepatic (and extrahepatic) damage by fatty acids and a great variety of their biologically active metabolites in a “multiple parallel-hit model”. This leads to inflammation and fibrogenesis and contributes to NAFLD progression. The alterations of the oxidant/antioxidant balance affect also metabolism-related organelles, leading to lipid peroxidation, mitochondrial dysfunction, and endoplasmic reticulum stress. This OS-induced damage is at least partially counteracted by the physiological antioxidant response. Therefore, modulation of this defense system emerges as an interesting target to prevent NAFLD development and progression. For instance, probiotics, prebiotics, diet, and fecal microbiota transplantation represent new therapeutic approaches targeting the gut microbiota dysbiosis. The OS and its counter-regulation are under the influence of individual genetic and epigenetic factors as well. In the near future, precision medicine taking into consideration genetic or environmental epigenetic risk factors, coupled with new OS biomarkers, will likely assist in noninvasive diagnosis and monitoring of NAFLD progression and in further personalizing treatments.
Collapse
Affiliation(s)
- Carlo Smirne
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Eleonora Croce
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Davide Di Benedetto
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Vincenzo Cantaluppi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Cristoforo Comi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Pier Paolo Sainaghi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Elena Grossini
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| |
Collapse
|
|
2
|
Gautheron J, Morisseau C, Chung WK, Zammouri J, Auclair M, Baujat G, Capel E, Moulin C, Wang Y, Yang J, Hammock BD, Cerame B, Phan F, Fève B, Vigouroux C, Andreelli F, Jeru I. EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence. eLife 2021; 10:68445. [PMID: 34342583 PMCID: PMC8331186 DOI: 10.7554/elife.68445] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 07/23/2021] [Indexed: 12/11/2022] Open
Abstract
Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. Metreleptin therapy had a beneficial effect in one patient. This translational study highlights the importance of epoxide regulation for adipocyte function and provides new insights into the physiological roles of EHs in humans.
Collapse
Affiliation(s)
- Jeremie Gautheron
- Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Christophe Morisseau
- Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, United States
| | - Wendy K Chung
- Department of Pediatrics, Columbia University Irving Medical Center, New York, United States.,Deparment of Medicine, Columbia University Irving Medical Center, New York, United States
| | - Jamila Zammouri
- Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Martine Auclair
- Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Genevieve Baujat
- Service de Génétique Clinique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | - Emilie Capel
- Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Celia Moulin
- Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Yuxin Wang
- Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, United States
| | - Jun Yang
- Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, United States
| | - Bruce D Hammock
- Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, United States
| | - Barbara Cerame
- Goryeb Children's Hospital, Atlantic Health Systems, Morristown Memorial Hospital, Morristown, United States
| | - Franck Phan
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.,Service de Diabétologie-Métabolisme, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France.,Sorbonne Université-Inserm UMRS_1269, Paris, France
| | - Bruno Fève
- Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.,Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service de Diabétologie et Endocrinologie de la Reproduction, Hôpital Saint-Antoine, AP-HP, Paris, France
| | - Corinne Vigouroux
- Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.,Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service de Diabétologie et Endocrinologie de la Reproduction, Hôpital Saint-Antoine, AP-HP, Paris, France.,Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, AP-HP, Paris, France
| | - Fabrizio Andreelli
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.,Service de Diabétologie-Métabolisme, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France.,Sorbonne Université-Inserm UMRS_1269, Paris, France
| | - Isabelle Jeru
- Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France.,Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.,Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, AP-HP, Paris, France
| |
Collapse
|
|
3
|
Wang D, Zhai JX, Zhang LM, Liu DW, Liu XH. EPHX1 Tyr113His polymorphism contributes to hepatocellular carcinoma risk: Evidence from a meta-analysis. Mol Biol 2015. [DOI: 10.1134/s0026893315020156] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
|
|
4
|
Jeng KS, Chang CF, Jeng WJ, Sheen IS, Jeng CJ. Heterogeneity of hepatocellular carcinoma contributes to cancer progression. Crit Rev Oncol Hematol 2015; 94:337-47. [PMID: 25680939 DOI: 10.1016/j.critrevonc.2015.01.009] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 10/24/2014] [Accepted: 01/21/2015] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous disease displaying differences in angiogenesis, extracellular matrix proteins, the immune microenvironment and tumor cell populations. Additionally, genetic variations and epigenetic changes of HCC cells could lead to aberrant signaling pathways, induce cancer stem cells and enhance tumor progression. Thus, the heterogeneity in HCC contributes to disease progression and a better understanding of its heterogeneity will greatly aid in the development of strategies for the HCC treatment.
Collapse
Affiliation(s)
- Kuo-Shyang Jeng
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
| | - Chiung-Fang Chang
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Wen-Juei Jeng
- Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, LinKou Medical Center, Chang Gung University, Taiwan
| | - I-Shyan Sheen
- Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, LinKou Medical Center, Chang Gung University, Taiwan
| | - Chi-Juei Jeng
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| |
Collapse
|
|
5
|
Carbonari D, Mansi A, Proietto AR, Paci E, Bonanni RC, Gherardi M, Gatto MP, Sisto R, Tranfo G. Influence of genetic polymorphisms of styrene-metabolizing enzymes on the levels of urinary biomarkers of styrene exposure. Toxicol Lett 2015; 233:156-62. [PMID: 25562543 DOI: 10.1016/j.toxlet.2015.01.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 12/27/2014] [Accepted: 01/02/2015] [Indexed: 11/27/2022]
Abstract
Styrene exposure is still present in different occupational settings including manufacture of synthetic rubber, resins, polyesters and plastic. The aim of this work was to investigate the effects of polymorphic genes CYP2E1, EPHX1, GSTT1, and GSTM1 on the urinary concentrations of the styrene metabolites mandelic acid (MA), phenylglyoxylic acid (PGA) and on the concentration ratios between (MA+PGA) and urinary styrene (U-Sty) and airborne styrene (A-Sty), in 30 workers from two fiberglass-reinforced plastic manufacturing plants and 26 unexposed controls. Personal air sampling and biological monitoring results revealed that sometimes exposure levels exceeded both the threshold limit value (TLV) and the biological exposure index (BEI) suggested by the American Conference of Governmental Industrial Hygienists. A significantly reduced excretion of styrene metabolites (MA+PGA) in individuals carrying the CYP2E1*5B and CYP2E1*6 heterozygote alleles, with respect to the homozygote wild type, was observed only in the exposed group. A reduction was also detected, in the same group, in subjects carrying the slow allele EPHX1 (codon 113), through the lowering of (MA+PGA)/urinary styrene concentration ratio. In addition, the ratio between MA+PGA and the personal airborne styrene concentration appeared to be modulated by the predicted mEH activity, in the exposed group, as evidenced by univariate linear regression analysis. Our results confirm some previous hypotheses about the role of the polymorphism of genes coding for enzymes involved in the styrene detoxification pathway: this may significantly reduce the levels of excreted metabolites and therefore it must be taken into account in the interpretation of the biological monitoring results for occupational exposure.
Collapse
Affiliation(s)
- Damiano Carbonari
- INAIL Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene Via di Fontana Candida 1, 00040 Monte Porzio Catone, Rome, Italy.
| | - Antonella Mansi
- INAIL Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene Via di Fontana Candida 1, 00040 Monte Porzio Catone, Rome, Italy.
| | - Anna Rita Proietto
- INAIL Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene Via di Fontana Candida 1, 00040 Monte Porzio Catone, Rome, Italy.
| | - Enrico Paci
- INAIL Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene Via di Fontana Candida 1, 00040 Monte Porzio Catone, Rome, Italy.
| | - Rossana Claudia Bonanni
- INAIL Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene Via di Fontana Candida 1, 00040 Monte Porzio Catone, Rome, Italy.
| | - Monica Gherardi
- INAIL Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene Via di Fontana Candida 1, 00040 Monte Porzio Catone, Rome, Italy.
| | - Maria Pia Gatto
- INAIL Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene Via di Fontana Candida 1, 00040 Monte Porzio Catone, Rome, Italy.
| | - Renata Sisto
- INAIL Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene Via di Fontana Candida 1, 00040 Monte Porzio Catone, Rome, Italy.
| | - Giovanna Tranfo
- INAIL Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene Via di Fontana Candida 1, 00040 Monte Porzio Catone, Rome, Italy.
| |
Collapse
|
|
6
|
El-Sherbeni AA, El-Kadi AOS. The role of epoxide hydrolases in health and disease. Arch Toxicol 2014; 88:2013-32. [PMID: 25248500 DOI: 10.1007/s00204-014-1371-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 09/11/2014] [Indexed: 01/09/2023]
Abstract
Epoxide hydrolases (EH) are ubiquitously expressed in all living organisms and in almost all organs and tissues. They are mainly subdivided into microsomal and soluble EH and catalyze the hydration of epoxides, three-membered-cyclic ethers, to their corresponding dihydrodiols. Owning to the high chemical reactivity of xenobiotic epoxides, microsomal EH is considered protective enzyme against mutagenic and carcinogenic initiation. Nevertheless, several endogenously produced epoxides of fatty acids function as important regulatory mediators. By mediating the formation of cytotoxic dihydrodiol fatty acids on the expense of cytoprotective epoxides of fatty acids, soluble EH is considered to have cytotoxic activity. Indeed, the attenuation of microsomal EH, achieved by chemical inhibitors or preexists due to specific genetic polymorphisms, is linked to the aggravation of the toxicity of xenobiotics, as well as the risk of cancer and inflammatory diseases, whereas soluble EH inhibition has been emerged as a promising intervention against several diseases, most importantly cardiovascular, lung and metabolic diseases. However, there is reportedly a significant overlap in substrate selectivity between microsomal and soluble EH. In addition, microsomal and soluble EH were found to have the same catalytic triad and identical molecular mechanism. Consequently, the physiological functions of microsomal and soluble EH are also overlapped. Thus, studying the biological effects of microsomal or soluble EH alterations needs to include the effects on both the metabolism of reactive metabolites, as well as epoxides of fatty acids. This review focuses on the multifaceted role of EH in the metabolism of xenobiotic and endogenous epoxides and the impact of EH modulations.
Collapse
Affiliation(s)
- Ahmed A El-Sherbeni
- Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, T6G 2E1, Canada
| | | |
Collapse
|
|
7
|
Carbonari D, Proietto A, Fioretti M, Tranfo G, Paci E, Papacchini M, Mansi A. Influence of genetic polymorphism on t,t-MA/S-PMA ratio in 301 benzene exposed subjects. Toxicol Lett 2014; 231:205-12. [PMID: 24968062 DOI: 10.1016/j.toxlet.2014.06.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 06/12/2014] [Accepted: 06/18/2014] [Indexed: 01/11/2023]
Abstract
This study investigated the effect of polymorphic genes GSTT1, GSTM1, GSTA1, EHPX1, NQO1, CYP2E1, CYP1A and MPO on the urinary concentrations and ratio (R) of the benzene metabolites trans,trans-muconic acid (t,t-MA) and S-phenyl mercapturic acid (S-PMA) in 301 oil refinery workers. The metabolites' concentrations are lower and R is higher (100.66) in non-smokers (n=184) than in smokers (n=117, R=36.54). Non-smokers have lower S-PMA and a higher R in GSTT1 null genotypes than in positive, and a higher S-PMA and a lower R in GSTA1 wild type genotypes. In smokers the GSTT1 null genotype effect on both S-PMA and R is confirmed, and is also shown in GSTM1 null, but not in GSTA1 wild type genotypes. GSTT1 null polymorphism reduces the conjugation rate of benzene epoxide with GSH, and to a lesser extent also GSTTA1 mutant, GSTM1 null and NQO1 mutant genotypes. The activity of one GST is compensated by another in GSTM1 and GSTA1 defective subjects, but not in GSTT1 null genotypes, whose average S-PMA excretion is about 50% with respect to the positive ones, for the same benzene exposure. R showed to be a more sensitive marker for these effects than the metabolite levels.
Collapse
Affiliation(s)
- Damiano Carbonari
- INAIL Research, Department of Occupational Hygiene, Via di Fontana Candida 1, 00040 Monteporzio Catone, Rome, Italy.
| | - Annarita Proietto
- INAIL Research, Department of Occupational Hygiene, Via di Fontana Candida 1, 00040 Monteporzio Catone, Rome, Italy
| | - Marzia Fioretti
- INAIL Research, Department of Occupational Hygiene, Via di Fontana Candida 1, 00040 Monteporzio Catone, Rome, Italy
| | - Giovanna Tranfo
- INAIL Research, Department of Occupational Medicine, Via di Fontana Candida 1, 00040 Monteporzio Catone, Rome, Italy.
| | - Enrico Paci
- INAIL Research, Department of Occupational Medicine, Via di Fontana Candida 1, 00040 Monteporzio Catone, Rome, Italy
| | - Maddalena Papacchini
- INAIL Research, Department for Production Plants and Interactions with the Environment, Via di Fontana Candida 1, 00040 Monteporzio Catone, Rome, Italy.
| | - Antonella Mansi
- INAIL Research, Department of Occupational Hygiene, Via di Fontana Candida 1, 00040 Monteporzio Catone, Rome, Italy.
| |
Collapse
|
|
8
|
Duan CY, Liu MY, Li SB, Ma KS, Bie P. Lack of association of EPHX1 gene polymorphisms with risk of hepatocellular carcinoma: a meta-analysis. Tumour Biol 2013; 35:659-66. [DOI: 10.1007/s13277-013-1090-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 08/05/2013] [Indexed: 12/17/2022] Open
|
|
9
|
Zhong JH, Xiang BD, Ma L, You XM, Li LQ, Xie GS. Meta-analysis of microsomal epoxide hydrolase gene polymorphism and risk of hepatocellular carcinoma. PLoS One 2013; 8:e57064. [PMID: 23451147 PMCID: PMC3581564 DOI: 10.1371/journal.pone.0057064] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Accepted: 01/17/2013] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Hepatocarcinogenesis is a complex process that may be influenced by many factors, including polymorphism in microsomal epoxide hydrolase (mEH). Previous work suggests an association between the Tyr113His and His139Arg mEH polymorphisms and susceptibility to hepatocellular carcinoma (HCC), but the results have been inconsistent. METHODS PubMed, EMBASE, Google Scholar and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. A meta-analysis was performed to examine the association between Tyr113His and His139Arg mEH polymorphism and susceptibility to HCC. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS Eleven studies were included in the meta-analysis, involving 1,696 HCC cases and 3,600 controls. The 113His- mEH allele was significantly associated with increased risk of HCC based on allelic contrast (OR = 1.35, 95% CI = 1.04-1.75, p = 0.02), homozygote comparison (OR = 1.65, 95% CI = 1.07-2.54, p = 0.02) and a recessive genetic model (OR = 1.54, 95% CI = 1.21-1.96, p<0.001), while individuals carrying the Arg139Arg mEH genotype had no association with increased or decreased risk of HCC. CONCLUSION The 113His- allele polymorphism in mEH may be a risk factor for hepatocarcinogenesis, while the mEH 139Arg- allele may not be a risk or protective factor. There is substantial evidence that mEH polymorphisms interact synergistically with other genes and the environment to modulate risk of HCC. Further large and well-designed studies are needed to confirm these conclusions.
Collapse
Affiliation(s)
- Jian-Hong Zhong
- Hepatobiliary Surgery Department, Tumor Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Bang-De Xiang
- Hepatobiliary Surgery Department, Tumor Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Liang Ma
- Hepatobiliary Surgery Department, Tumor Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Xue-Mei You
- Hepatobiliary Surgery Department, Tumor Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Le-Qun Li
- Hepatobiliary Surgery Department, Tumor Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Gui-Sheng Xie
- General Surgery Department, The Third Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| |
Collapse
|
|
10
|
Holmes JA, Thompson AJ, Adams LA. Biomarkers of Fibrosis and Fibrosis Progression in Chronic Hepatitis C. CURRENT HEPATITIS REPORTS 2012; 11:231-242. [DOI: 10.1007/s11901-012-0148-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
11
|
Rahat B, Kiran M, Saxena R, Chawla YK, Sharma RR, Kaur J. Microsomal Epoxide Hydrolase Polymorphisms and Haplotypes as Determinants of Hepatitis B Virusand Hepatitis C Virus-related Liver Disease in Indian Population. J Clin Exp Hepatol 2012; 2:104-111. [PMID: 25755418 PMCID: PMC3940147 DOI: 10.1016/s0973-6883(12)60097-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Accepted: 05/08/2012] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the fifth most common cancer and third leading cause of death worldwide. Main causes of HCC are hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. mEPHX, a xenobiotic metabolizing enzyme, exhibits a dual role of procarcinogen detoxification and activation, hence considered as a cancer risk factor as well as a protective factor. Two known polymorphic forms of mEPHX, exon in exon 3 and 4, are associated with the development of HCC. OBJECTIVE To determine the association of genotypes and haplotypes of mEPHX with risk of HCC developments separately in HBV- and HCV-infected carriers and patients with hepatitis. METHODS Polymerase chain reactions (PCR) were carried out using primers to amplify exon 3 (113 Tyr→His variant) and exon 4 (139 His→Arg) polymorphic sites. To distinguish the wild and variant forms, PCR amplification products were digested with restriction endonucleases EcoRV and Rsa1 for exons 3 and 4, respectively. RESULT Exon 3 genotypes, Y113H and H113H, shared a protective association with HBV-chronic hepatitis infection (P < 0.001 and P< 0.01, respectively) as well as HBV-HCC development (P < 0.001) among HBV-carrier group, while Y113H acts as a risk factor for HCV-chronic hepatitis development (P < 0.001) as well as for HCC development (P < 0.01) with HCV-carrier group as reference. Both H139R and R139R, exon 4 genotypes, acted as a risk factor for HBV/HCV-chronic hepatitis infection and for HBV/HCV-HCC development (P ranges from < 0.05 to < 0.001) with HBV/HCV carriers as reference. 113His-139His and 113His-139Arg haplotypes shared a significant negative and positive association, respectively, with HBV hepatitis and HBV-HCC risk. 113Tyr-139Arg haplotype acted as a risk for HCV-HCC development. CONCLUSION Polymorphic and haplotypic variant forms of mEPHX exon 3 and 4 variably determine the susceptibility to develop HCC in HBV- and HCV-carrier subjects.
Collapse
Affiliation(s)
- Beenish Rahat
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh – 160012, India
| | - Manjula Kiran
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh – 160012, India
| | - Roli Saxena
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh – 160012, India
| | - Yogesh K Chawla
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh – 160012, India
| | - Rati R Sharma
- Department of Transfusion Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh – 160012, India
| | - Jyotdeep Kaur
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh – 160012, India
| |
Collapse
|
|
12
|
Duan H, Yoshimura K, Kobayashi N, Sugiyama K, Sawada JI, Saito Y, Morisseau C, Hammock BD, Akatsuka T. Development of monoclonal antibodies to human microsomal epoxide hydrolase and analysis of "preneoplastic antigen"-like molecules. Toxicol Appl Pharmacol 2012; 260:17-26. [PMID: 22310175 DOI: 10.1016/j.taap.2012.01.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2011] [Revised: 01/20/2012] [Accepted: 01/22/2012] [Indexed: 01/13/2023]
Abstract
Microsomal epoxide hydrolase (mEH) is a drug metabolizing enzyme which resides on the endoplasmic reticulum (ER) membrane and catalyzes the hydration of reactive epoxide intermediates that are formed by cytochrome P450s. mEH is also thought to have a role in bile acid transport on the plasma membrane of hepatocytes. It is speculated that efficient execution of such multiple functions is secured by its orientation and association with cytochrome P450 enzymes on the ER membrane and formation of a multiple transport system on the plasma membrane. In certain disease status, mEH loses its association with the membrane and can be detected as distinct antigens in the cytosol of preneoplastic foci of liver (preneoplastic antigen), in the serum in association with hepatitis C virus infection (AN antigen), or in some brain tumors. To analyze the antigenic structures of mEH in physiological and pathological conditions, we developed monoclonal antibodies against different portions of mEH. Five different kinds of antibodies were obtained: three, anti-N-terminal portions; one anti-C-terminal; and one, anti-conformational epitope. By combining these antibodies, we developed antigen detection methods which are specific to either the membrane-bound form or the linearized form of mEH. These methods detected mEH in the culture medium released from a hepatocellular carcinoma cell line and a glioblastoma cell line, which was found to be a multimolecular complex with a unique antigenic structure different from that of the membrane-bound form of mEH. These antibodies and antigen detection methods may be useful to study pathological changes of mEH in various human diseases.
Collapse
Affiliation(s)
- Hongying Duan
- Department of Microbiology, Faculty of Medicine, Saitama Medical University, Moroyama-cho, Iruma-gun, Saitama 350-0495, Japan
| | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Matas M, Picornell A, Cifuentes C, Payeras A, Bassa A, Homar F, López-Labrador FX, Moya A, Ramon MM, Castro JA. Relating the liver damage with hepatitis C virus polymorphism in core region and human variables in HIV-1-coinfected patients. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2010; 10:1252-1261. [PMID: 20732459 DOI: 10.1016/j.meegid.2010.08.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2010] [Revised: 08/14/2010] [Accepted: 08/16/2010] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infection is the most important cause of chronic hepatitis, cirrhosis and end-stage liver disease leading to liver transplantation worldwide. Chronic infection by HCV causes liver fibrosis, which is accelerated by unknown mechanisms in patients with human immunodeficiency virus-1 (HIV-1) coinfection. Although the genetic variability of both HCV and HIV has been extensively studied in the context of monoinfections, more limited data is available regarding HCV-HIV coinfection. HCV disease progression among HIV coinfected patients may be influenced not only by demographic, epidemiological and clinical background variables, but also by genetic differences in infecting viruses. To explore this issue, we carried out a study in coinfected patients trying to associate the degree of liver damage to several demographic, clinical, and epidemiological characteristics of the patients, and also to the genetic variability of HCV between patients. For this purpose, we have applied different statistical techniques including the statistical generalized linear model (GLM) framework. The stage of fibrosis was indirectly measured by noninvasive means using the indexes Forns, APRI and FIB-4. HCV genetic variability between patients was estimated by sequencing the core region and by reconstructions of consensus maximum parsimony phylogenetic trees with 50% and 75% bootstrap majority rules. The results showed a direct correlation of the fibrosis biomarkers with the AST/ALT ratio, MoftIDU and with 3a HCV genotype clades, among others.
Collapse
Affiliation(s)
- Marina Matas
- Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS) i Laboratori de Genètica, Departament de Biologia, Universitat de les Illes Balears, Campus de la UIB, Palma de Mallorca, Illes Balears, Spain
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
14
|
Kiran M, Chawla YK, Jain M, Kaur J. Haplotypes of microsomal epoxide hydrolase and x-ray cross-complementing group 1 genes in Indian hepatocellular carcinoma patients. DNA Cell Biol 2009; 28:573-577. [PMID: 19754350 DOI: 10.1089/dna.2009.0921] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a life-threatening disease that is often associated with chronic infection by hepatitis B and C viruses. Genetic polymorphisms have been reported to alter the risk for HCC development. Genetic studies based on the haplotype have an increased power for detecting disease associations compared with single-nucleotide polymorphism-based analysis. There is sufficient epidemiological evidence suggesting a link between genetic polymorphism and haplotypes of microsomal epoxide hydrolase (mEPHX) and X-ray cross-complementing group 1 (XRCC1) with altered cancer risk. However, no report correlates the risk of HCC development with mEPHX and XRCC1 haplotypes. Genetic polymorphism of these genes was studied for haplotype construction in 169 control subjects, 174 hepatitis patients, and 63 HCC patients. 113Tyr-139Arg and 113His-139His haplotypes of mEPHX significantly elevated the risk for HCC by 1.4- and 1.5-folds, respectively. Arg-His-Arg haplotype of XRCC1 significantly enhanced the risk for hepatitis by 2.8-folds (p = 0.001), but not for HCC (odds ratio = 1.5; p = 0.28). mEPHX haplotypes shared a positive association with HCC risk in India.
Collapse
Affiliation(s)
- Manjula Kiran
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | | | | | | |
Collapse
|
|
15
|
Li C, Kato N, Chang J, Muroyama R, Shao R, Dharel N, Sermsathanasawadi R, Kawabe T, Omata M. Polymorphism of OAS-1 determines liver fibrosis progression in hepatitis C by reduced ability to inhibit viral replication. Liver Int 2009; 29:1413-21. [PMID: 19515215 PMCID: PMC7194156 DOI: 10.1111/j.1478-3231.2009.02061.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Progression of disease after hepatitis C virus (HCV) infection differs among individuals, indicating a possibility of participation of host genetic factors. 2'-5'-oligoadenylate synthetase 1 (OAS-1), an important component of the innate immune system, has an antiviral function, and may therefore have a certain relationship with progression of disease. AIM To evaluate single nucleotide polymorphisms (SNPs) of OAS-1 and its relationship with the disease status of HCV infection. METHODS Six SNPs of OAS-1 were selected and examined in 409 Japanese patients with chronic HCV infection using the TaqMan PCR genotyping method. The relationship of SNP genotypes and clinical manifestations of patients was analysed. Then, a pair of OAS-1-expression plasmids mimicking the clinical-related SNPs were created and transfected into liver cells carrying the HCV subgenomic replicon or the full-length genome, JFH1, and HCV replication after transfection was compared. RESULTS Patients with genotypes A/A, A/G and G/G of an SNP of OAS-1 at the exon 3 of its coding sequence were at gradient increased risks of suffering from higher serum alanine aminotransferase (P<0.001) and aspartate aminotransferase (P=0.001), higher degree of liver fibrosis (P=0.010) and higher presence of liver cirrhosis (P=0.001). By multivariate logistic regression analysis, genotype G/G was an independent factor associated with cirrhosis (P=0.013, odds ratio 3.11, 95% confidence interval 1.27-7.63). In liver cells, OAS-1 with the G allele showed lower ability to inhibit virus replication than OAS-1 with the A allele (P=0.004). CONCLUSIONS The SNP of OAS-1 at the exon 3 of its coding sequence was associated with progression of disease in Japanese patients with HCV infection.
Collapse
Affiliation(s)
- Chang‐Zheng Li
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan,Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan,Unit of Disease Control Genome Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Jin‐Hai Chang
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Ryosuke Muroyama
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan,Unit of Disease Control Genome Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Run‐Xuan Shao
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Narayan Dharel
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | | | - Takao Kawabe
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Masao Omata
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
16
|
Navaneethan U, Kemmer N, Neff GW. Predicting the probable outcome of treatment in HCV patients. Therap Adv Gastroenterol 2009; 2:287-302. [PMID: 21180557 PMCID: PMC3002533 DOI: 10.1177/1756283x09339079] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Hepatitis C virus (HCV) is a major cause of chronic liver disease infecting more than 170 million people worldwide. HCV produces a wide gamut of manifestations varying from mild self-limiting disease to cirrhosis and hepatocellular carcinoma. A variety of viral, environmental and host genetic factors contribute to the clinical spectrum of patients infected with HCV and influence response to interferon (IFN) therapy. Predicting the probable outcome of treatment in patients with HCV infection has always been a challenging task. Treatment of HCV by pegylated interferon (peg-IFN) plus ribavirin eradicates the virus in approximately 60% of patients - HCV genotype 1 (42-51% response rates) and genotypes 2 and 3 (76-84% response rates); however, a significant number of patients do not respond to therapy or relapse following discontinuation of treatment or have significant side effects that preclude further treatment. Accurately predicting the patients who will respond to therapy is becoming increasingly important, both from the point of patient care and also with respect to the healthcare cost as clinicians need to continue treatment in patients who will respond and stop treatment in patients who are unlikely to respond. Viral RNA measurements and genotyping are used to optimize treatment as a low viral load and nongenotype 1 is more likely to be associated with sustained virological response (SVR). Rapid virological response (RVR) defined by undetectable HCV RNA at 4 weeks of treatment is increasingly being recognized as a powerful tool for predicting treatment response. A variety of host factors including single nuclear polymorphisms (SNPs) of IFN response genes, insulin resistance, obesity, ethnicity, human leukocyte antigens and difference in T-cell immune response has been found to modulate the response to antiviral treatment. The presence of severe fibrosis/cirrhosis on pretreatment liver biopsy predicts a poor response to treatment. Recent studies on gene expression profiling and characterization of the liver and serum proteome provide options to accurately predict the outcome of patients infected with HCV in the future. Future studies on the factors that predict treatment response and tailoring treatment based on this is required if we are to conquer this disease.
Collapse
Affiliation(s)
- Udayakumar Navaneethan
- Department of Internal Medicine, University of Cincinnati College of
Medicine, Cincinnati, Ohio, USA
| | - Nyingi Kemmer
- Division of Digestive Diseases, University of Cincinnati College of
Medicine, Cincinnati, Ohio, USA
| | - Guy W. Neff
- Division of Digestive Diseases, University of Cincinnati College of
Medicine, Cincinnati, Ohio, USA
| |
Collapse
|
|
17
|
Minisini R, Fabris C, Toniutto P, Pirisi M. Combinatorial use of single nucleotide polymorphisms to help predict liver fibrosis in patients with hepatitis C infections. ACTA ACUST UNITED AC 2009; 3:355-70. [DOI: 10.1517/17530050902893311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
|
|
18
|
Kiran M, Chawla YK, Kaur J. Glutathione-S-transferase and microsomal epoxide hydrolase polymorphism and viral-related hepatocellular carcinoma risk in India. DNA Cell Biol 2008; 27:687-694. [PMID: 18816171 DOI: 10.1089/dna.2008.0805] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common cancer worldwide, the main etiological factors being chronic infections with hepatitis B and C viruses. Genetic polymorphic forms of glutathione-S-transferase (GST) and microsomal epoxide hydrolase (mEPHX) have been associated with risk for various malignancies. The present study was undertaken to evaluate the association of GSTT1 and GSTM1 null genotypes and mEPHX polymorphisms with hepatitis virus-related HCC risk in an Indian population. Three groups of subjects were considered, control (n = 169), chronic viral hepatitis (n = 174), and HCC (n = 63). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for this polymorphic study. Genotype distributions between categories were compared using the chi2 test; odds ratios (ORs) and 95% confidence interval were calculated to express the relative risk. GSTT1 null genotype was associated with 2.23-fold (p < 0.05) increased risk for HCC development as compared to the control group. However, GSTM1 null genotype was found to have a protective effect when hepatitis patients were considered. In case of mEPHX, R139R imposed a risk factor for HCC with both control (OR = 1.81) and chronic hepatitis-infected (OR = 2.06) subjects. Combination of heterozygous mutant genotypes at mEPHX exons 3 and 4 revealed a twofold risk (nonsignificant) for HCC. Further, combination of GSTM1 and T1 genotypes with either of exon 3 or 4 polymorphism of mEPHX displayed synergistic associations (risk or protective) for HCC development. GST and mEPHX variants share a positive association with viral-related HCC risk in Indian population, although a larger sample size is still required to confirm the results.
Collapse
Affiliation(s)
- Manjula Kiran
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | | |
Collapse
|
|
19
|
Dail MB, Shack LA, Chambers JE, Burgess SC. Global liver proteomics of rats exposed for 5 days to phenobarbital identifies changes associated with cancer and with CYP metabolism. Toxicol Sci 2008; 106:556-69. [PMID: 18796496 PMCID: PMC2581678 DOI: 10.1093/toxsci/kfn198] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2008] [Accepted: 09/10/2008] [Indexed: 12/14/2022] Open
Abstract
A global proteomics approach was applied to model the hepatic response elicited by the toxicologically well-characterized xenobiotic phenobarbital (PB), a prototypical inducer of hepatic xenobiotic metabolizing enzymes and a well-known nongenotoxic liver carcinogen in rats. Differential detergent fractionation two-dimensional liquid chromatography electrospray ionization tandem mass spectrometry and systems biology modeling were used to identify alterations in toxicologically relevant hepatic molecular functions and biological processes in the livers of rats following a 5-day exposure to PB at 80 mg/kg/day or a vehicle control. Of the 3342 proteins identified, expression of 121 (3.6% of the total proteins) was significantly increased and 127 (3.8%) significantly decreased in the PB group compared to controls. The greatest increase was seen for cytochrome P450 (CYP) 2B2 (167-fold). All proteins with statistically significant differences from control were then analyzed using both Gene Ontology (GO) and Ingenuity Pathways Analysis (IPA, 5.0 IPA-Tox) for cellular location, function, network connectivity, and possible disease processes, especially as they relate to CYP-mediated metabolism and nongenotoxic carcinogenesis mechanisms. The GO results suggested that PB's mechanism of nongenotoxic carcinogenesis involves both increased xenobiotic metabolism, especially induction of the 2B subfamily of CYP enzymes, and increased cell cycle activity. Apoptosis, however, also increased, perhaps, as an attempt to counter the rising cancer threat. Of the IPA-mapped proteins, 41 have functions which are procarcinogenic and 14 anticarcinogenic according to the hypothesized nongenotoxic mechanism of imbalance between apoptosis and cellular proliferation. Twenty-two additional IPA nodes can be classified as procarcinogenic by the competing theory of increased metabolism resulting in the formation of reactive oxygen species. Since the systems biology modeling corresponded well to PB effects previously elucidated via more traditional methods, the global proteomic approach is proposed as a new screening methodology that can be incorporated into future toxicological studies.
Collapse
Affiliation(s)
- Mary B. Dail
- Center for Environmental Health Sciences, College of Veterinary Medicine
- Department of Basic Sciences, College of Veterinary Medicine
| | - L. Allen Shack
- Department of Basic Sciences, College of Veterinary Medicine
| | - Janice E. Chambers
- Center for Environmental Health Sciences, College of Veterinary Medicine
- Department of Basic Sciences, College of Veterinary Medicine
| | - Shane C. Burgess
- Department of Basic Sciences, College of Veterinary Medicine
- Mississippi Agriculture and Forestry Experiment Station
- Institute for Digital Biology
- Life Sciences and Biotechnology Institute, Mississippi State University, Mississippi State, Mississippi 39762
| |
Collapse
|
|
20
|
Feo F, Frau M, Pascale RM. Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis. World J Gastroenterol 2008; 14:6601-15. [PMID: 19034960 PMCID: PMC2773299 DOI: 10.3748/wjg.14.6601] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Studies on rodents and humans demonstrate an inherited predisposition to hepatocellular carcinoma (HCC). Analysis of the molecular alterations involved in the acquisition of a phenotype resistant or susceptible to hepatocarcinogenesis showed a deregulation of G1 and S phases in HCC of genetically susceptible F344 rats and a G1-S block in lesions of resistant Brown norway (BN) rats. Unrestrained extracellular signal-regulated kinase (ERK) activity linked to proteasomal degradation of dual-specificity phosphatase 1 (DUSP1), a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex occurs in more aggressive HCC of F344 rats and humans. This mechanism is less active in HCC of BN rats and human HCC with better prognosis. Upregulation of iNos cross-talk with IKK/NF-κB and RAS/ERK pathways occurs in rodent liver lesions at higher levels in the most aggressive models represented by HCC of F344 rats and c-Myc-TGF-α transgenic mice. iNOS, IKK/NF-κB, and RAS/ERK upregulation is highest in human HCC with a poorer prognosis and positively correlates with tumor proliferation, genomic instability and microvascularization, and negatively with apoptosis. Thus, cell cycle regulation and the activity of signal transduction pathways seem to be modulated by HCC modifier genes, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.
Collapse
|
|
21
|
Morgan TR, Lambrecht RW, Bonkovsky HL, Chung RT, Naishadham D, Sterling RK, Fontana RJ, Lee WM, Ghany MG, Wright EC, O'Brien TR. DNA polymorphisms and response to treatment in patients with chronic hepatitis C: results from the HALT-C trial. J Hepatol 2008; 49:548-56. [PMID: 18619701 PMCID: PMC3903339 DOI: 10.1016/j.jhep.2008.05.011] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2007] [Revised: 05/04/2008] [Accepted: 05/08/2008] [Indexed: 12/16/2022]
Abstract
BACKGROUND/AIMS Certain host genetic polymorphisms reportedly affect the likelihood of a sustained virological response (SVR) to interferon treatment in subjects infected with hepatitis C virus (HCV). As part of the HALT-C trial we evaluated genetic associations among patients infected with HCV genotype 1 who had failed previous interferon treatment. METHODS SVR was determined 24 weeks after completing treatment with pegylated interferon alfa-2a and ribavirin. Eight single nucleotide polymorphisms (SNPs) were selected on the basis of previously reported associations with treatment response. Genotypes were assessed by polymerase chain reaction-based assays. The percentage of patients who achieved SVR was determined for each genotype and for an IL10 promoter diplotype. RESULTS Among 637 non-Hispanic Caucasian patients there were no significant associations between genotype for any individual SNP (IL10-1082, IL10-592, TNF-308, TNF-238, TGFB1 codon 25, CCL2-2518, EPHX1 codon 113 and AGT-6) and SVR, but SVR was more common among the patients who were homozygous for the ACC IL10 promoter diplotype (adjusted odds ratio, 3.24; 95% confidence interval, 1.33-7.78; p=0.001). CONCLUSIONS Among non-Hispanic Caucasian patients treated with peginterferon and ribavirin after failing previous treatment with interferon, homozygosity for the ACC IL10 promoter diplotype was associated with SVR.
Collapse
Affiliation(s)
- Timothy R Morgan
- Division of Gastroenterology, University of California Irvine, Irvine, CA, USA.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Halangk J, Sarrazin C, Neumann K, Puhl G, Mueller T, Teuber G, Klinker H, Hinrichsen H, Buggisch P, Landt O, Weich V, Bergk A, Wiedenmann B, Neuhaus P, Berg T, Witt H. Evaluation of complement factor 5 variants as genetic risk factors for the development of advanced fibrosis in chronic hepatitis C infection. J Hepatol 2008; 49:339-45. [PMID: 18644651 DOI: 10.1016/j.jhep.2008.05.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2007] [Revised: 04/24/2008] [Accepted: 05/27/2008] [Indexed: 12/28/2022]
Abstract
BACKGROUND/AIMS Intercross studies in inbred mice susceptible or resistant to liver fibrosis revealed complement factor 5 as a quantitative trait gene associated with the development of fibrosis. In 277 patients with hepatitis C, two C5 SNPs, rs17611 and rs2300929, have been associated with advanced fibrosis. METHODS We investigated the association of these C5 SNPs with advanced fibrosis in 1435 HCV infected patients and in 1003 patients with other liver diseases. We performed genotyping with melting curve analysis using fluorescence resonance energy transfer probes in the LightCycler. RESULTS The defined high-risk genotypes (AA and TT) and alleles (A and T) were not associated with advanced fibrosis in HCV patients when Chi square testing and logistic regression analysis were applied (rs17611A 0.45 in F0-1 vs. 0.43 in F2-4, P=0.31; rs2300929T 0.91 F0-1 and 0.91 in F2-4, P=0.82). In the group of patients with liver diseases other than HCV we neither found an association of the C5 SNPs with advanced fibrosis nor an overrepresentation of the SNPs in patients with cirrhosis. CONCLUSIONS We found no evidence that these C5 SNPs are genetic risk factors for the development of advanced fibrosis in chronic HCV infection or other chronic liver diseases.
Collapse
Affiliation(s)
- Juliane Halangk
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Germany
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Missiha SB, Ostrowski M, Heathcote EJ. Disease progression in chronic hepatitis C: modifiable and nonmodifiable factors. Gastroenterology 2008; 134:1699-714. [PMID: 18471548 DOI: 10.1053/j.gastro.2008.02.069] [Citation(s) in RCA: 159] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2007] [Revised: 02/15/2008] [Accepted: 02/21/2008] [Indexed: 12/13/2022]
Abstract
The hepatic complications of chronic hepatitis C (CHC) usually occur only after progression to cirrhosis has taken place. Progression to cirrhosis, however, is extremely variable and depends on a broad set of host and viral factors that modify the rate at which fibrosis develops in a given individual. Despite their inherent limitations, studies of the natural history of CHC have identified several nonmodifiable factors associated with disease progression. These include age at acquisition of infection, sex, and race. More recent reports suggest important roles for host genetic polymorphisms and viral factors. Of greater immediate relevance to patients and their clinicians are the potentially modifiable factors, which include excessive alcohol consumption; smoking (tobacco and marijuana); insulin resistance; and coinfection with hepatitis B virus, human immunodeficiency virus type 1, or schistosomiasis. Unfortunately, to date, there are no reliable predictive models that can accurately estimate the risk of CHC disease progression.
Collapse
Affiliation(s)
- Sharif B Missiha
- Division of Gastroenterology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | | | | |
Collapse
|
|
24
|
Gressner OA, Weiskirchen R, Gressner AM. Biomarkers of hepatic fibrosis, fibrogenesis and genetic pre-disposition pending between fiction and reality. J Cell Mol Med 2008; 11:1031-51. [PMID: 17979881 PMCID: PMC4401271 DOI: 10.1111/j.1582-4934.2007.00092.x] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Fibrosis is a frequent, life-threatening complication of most chronic liver diseases. Despite major achievements in the understanding of its pathogenesis, the translation of this knowledge into clinical practice is still limited. In particular, non-invasive and reliable (serum-) biomarkers indicating the activity of fibrogenesis are scarce. Class I biomarkers are defined as serum components having a direct relation to the mechanism of fibrogenesis, either as secreted matrix-related components of activated hepatic stellate cells and fibroblasts or as mediators of extracellular matrix (ECM) synthesis or turnover. They reflect primarily the activity of the fibrogenic process. Many of them, however, proved to be disappointing with regard to sensitivity and speci-ficity. Up to now hyaluronan turned out to be the relative best type I serum marker. Class II biomarkers comprise in general rather simple standard laboratory tests, which are grouped into panels. They fulfil most criteria for detection and staging of fibrosis and to a lesser extent grading of fibrogenic activity. More than 20 scores are currently available, among which Fibrotest™ is the most popular one. However, the diagnostic use of many of these scores is still limited and standardization of the assays is only partially realized. Combining of panel markers in sequential algorithms might increase their diagnostic validity. The translation of genetic pre-disposition biomarkers into clinical practice has not yet started, but some polymorphisms indicate a link to progression and outcome of fibrogenesis. Parallel to serum markers non-invasive physical techniques, for example, transient elastography, are developed, which can be combined with serum tests and profiling of serum proteins and glycans.
Collapse
Affiliation(s)
- O A Gressner
- Institute of Clinical Chemistry and Pathobiochemistry, Central Laboratory, RWTH-University Hospital, Aachen, Germany.
| | | | | |
Collapse
|
|
25
|
Schott E, Witt H, Neumann K, Taube S, Oh DY, Schreier E, Vierich S, Puhl G, Bergk A, Halangk J, Weich V, Wiedenmann B, Berg T. A Toll-like receptor 7 single nucleotide polymorphism protects from advanced inflammation and fibrosis in male patients with chronic HCV-infection. J Hepatol 2007; 47:203-11. [PMID: 17512627 DOI: 10.1016/j.jhep.2007.03.021] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2007] [Revised: 03/05/2007] [Accepted: 03/20/2007] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIMS HCV-infection leads to development of liver fibrosis, causing morbidity and mortality. Multiple factors influence the progression of fibrosis, including genetic factors. Since HCV is an RNA virus, a role for TLR7 in the immune response against HCV is likely. No systematic analysis of TLR7 single nucleotide polymorphisms (SNPs) has been published. METHODS We sequenced TLR7 in 52 women and investigated SNPs with an allele frequency >5% in 807 patients with chronic HCV-infection by melting curve analysis. We analyzed the effect of TLR7 SNPs on grade of inflammation and stage of fibrosis as determined by liver biopsy. RESULTS We detected five TLR7 SNPs, three of which showed a frequency >5%. One variant, c.1-120T>G, was more common in patients with no or little inflammation than in patients with grades 2-4 (10.7% vs. 6.1%; P=0.034). The variant was also enriched in patients with no or little fibrosis compared to those with higher stages (12.6% vs. 6.6%; P=0.005). The difference was fully attributable to male patients. CONCLUSIONS This is the first analysis of TLR7 SNPs in patients with chronic HCV-infection. Our data suggest that the c.1-120G TLR7 allele offers protection from the development of inflammation and fibrosis in male patients with chronic HCV-infection.
Collapse
Affiliation(s)
- Eckart Schott
- Department of Hepatology and Gastroenterology, CVK, Charité Universitätsmedizin Berlin, Germany
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Ada AO, Suzen HS, Iscan M. Polymorphisms of microsomal epoxide hydrolase and glutathione S-transferase P1 in a male Turkish population. Int J Toxicol 2007; 26:41-6. [PMID: 17365145 DOI: 10.1080/10915810601118222] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Polymorphic genes encoding drug-metabolizing enzymes may account for interindividual differences in certain types of diseases especially cancer. In this study, microsomal epoxide hydrolase (EPHX1) and glutathione S-transferase P1 (GSTP1) gene polymorphisms were determined among 133 healthy males of a Turkish population. Frequencies of EPHX1 and GSTP1 gene polymorphisms were determined by using the polymerase chain reaction-restriction fragment length polymorphism (PCR/RFLP) method. The observed genotype frequencies of EPHX1 exon 3 were Tyr113Tyr:50.4%, Tyr113His: 42.1%, His113His: 7.5% and EPHX1 exon 4 were His139His: 69.2%, His139Arg: 28.6%, Arg133Arg: 2.2%. GSTP1 exon 5 genotype frequencies were Ile105Ile: 58.7%, Ile105Val: 35.3%, Val105Val: 6.0% and GSTP1 exon 6 genotype frequencies were Ala114Ala: 85.0%, Ala114Val: 14.3%, Val114Val: 0.7%. These results reveal that the frequencies of EPHX1 and GSTP1gene polymorphisms in a small sampling of males within a Turkish population are similar to European Caucasian populations.
Collapse
Affiliation(s)
- Ahmet O Ada
- Department of Toxicology, School of Pharmacy, Ankara University, Ankara, Turkey.
| | | | | |
Collapse
|
|
27
|
Akatsuka T, Kobayashi N, Ishikawa T, Saito T, Shindo M, Yamauchi M, Kurokohchi K, Miyazawa H, Duan H, Matsunaga T, Komoda T, Morisseau C, Hammock BD. Autoantibody response to microsomal epoxide hydrolase in hepatitis C and A. J Autoimmun 2007; 28:7-18. [PMID: 17296285 PMCID: PMC1892246 DOI: 10.1016/j.jaut.2006.12.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2006] [Revised: 12/17/2006] [Accepted: 12/18/2006] [Indexed: 12/12/2022]
Abstract
Autoimmune responses were observed in a large proportion of hepatitis C cases and are suspected to be part of viral pathogenesis. The AN6520 antigen (AN-Ag) is a normal cellular protein mainly expressed in liver that was found associated with non-A, non-B hepatitis. To elucidate its pathogenic role in hepatitis C, we developed an IgM capture assay using purified AN-Ag and confirmed that the antibody response to AN-Ag is associated almost exclusively with hepatitis C cases (29%). Screening of a human liver expression library revealed that AN-Ag is mainly the microsomal epoxide hydrolase (mEH), a drug-metabolizing enzyme that plays an important role in the metabolism of some mutagenic and carcinogenic epoxides. Using the purified recombinant human mEH as an antigen, we now found that antibodies against this protein are associated with nearly 82% of hepatitis C virus infections and surprisingly with 46% of patients with hepatitis A. The appearance of AN-Ag/mEH in the incubation period of hepatitis C as previously reported and the antibody responses shown here indicate that this enzyme may be a marker for or even a cause of some of the pathology associated with hepatitis C and A.
Collapse
Affiliation(s)
- Toshitaka Akatsuka
- Department of Microbiology, Saitama Medical University, Moroyama-cho, Iruma-gun, Saitama 350-0495, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Su LJ, Ding GW, Yang ZL, Zhang SB, Yang YX, Xu CS. Expression patterns and action analysis of genes associated with hepatitis virus infection during rat liver regeneration. World J Gastroenterol 2006; 12:7626-34. [PMID: 17171791 PMCID: PMC4088044 DOI: 10.3748/wjg.v12.i47.7626] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the action of hepatitis virus infection-associated genes at transcription level during liver regeneration (LR).
METHODS: Hepatitis virus infection-associated genes were obtained by collecting the data from databases and retrieving the correlated articles, and their expression changes in the regenerating rat liver were detected with the rat genome 230 2.0 array.
RESULTS: Eighty-eight genes were found to be associated with liver regeneration. The number of genes initially and totally expressed during initial LR [0.5-4 h after partial hepatectomy (PH)], transition from G0 to G1 (4-6 h after PH), cell proliferation (6-66 h after PH), cell differentiation and reorganization of structure-function (66-168 h after PH) was 37, 8, 48, 3 and 37, 26, 80, 57, respectively, indicating that the genes were mainly triggered at the early stage of LR (0.5-4 h after PH), and worked at different phases. These genes were classified into 5 types according to their expression similarity, namely 37 up-regulated, 9 predominantly up-regulated, 34 down-regulated, 6 predominantly down-regulated and 2 up/down-regulated genes. Their total up- and down-regulation frequencies were 359 and 149 during LR, indicating that the expression of most genes was enhanced, while the expression of a small number of genes was attenuated during LR. According to time relevance, they were classified into 12 groups (0.5 and 1 h, 2 and 4 h, 6 h, 8 and 12 h, 16 and 96 h, 18 and 24 h, 30 and 42 h, 36 and 48 h, 54 and 60 h, 66 and 72 h, 120 and 144 h, 168 h), demonstrating that the cellular physiological and biochemical activities during LR were fluctuated. According to expression changes of the genes, their expression patterns were classified into 23 types, suggesting that the cellular physiological and biochemical activities during LR were diverse and complicated.
CONCLUSION: The anti-virus infection capacity of regenerating liver can be enhanced and 88 genes play an important role in LR.
Collapse
Affiliation(s)
- Li-Juan Su
- Faculty of Life Science and Technology, Ocean University of China, Qingdao 260003, Shandong Province, China
| | | | | | | | | | | |
Collapse
|
|
29
|
McGovern BH, Wurcel A, Kim AY, Schulze zur Wiesch J, Bica I, Zaman MT, Timm J, Walker BD, Lauer GM. Acute hepatitis C virus infection in incarcerated injection drug users. Clin Infect Dis 2006; 42:1663-70. [PMID: 16705568 DOI: 10.1086/504327] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2005] [Accepted: 02/11/2006] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND The Centers for Disease Control and Prevention has emphasized the need for interventional programs regarding hepatitis C virus (HCV) infection for injection drug users, the group of persons who are at highest risk of acquiring acute infection. METHODS We designed a pilot study to assess the feasibility of identifying injection drug users with acute HCV infection in correctional and detoxification facilities. On-site medical providers were educated regarding risk factors and signs and symptoms of infection and were instructed to refer all patients with hepatitis to our specialty clinic. RESULTS Over a 30-month period, 21 patients received a diagnosis of acute hepatitis C, 3 received a diagnosis of hepatitis B, and 1 received a diagnosis of hepatitis A. Of the 21 patients with acute hepatitis C, 19 were identified in the prison setting shortly after incarceration. Of the 17 patients who were observed serially (mean duration of observation, 6.3 months), 8 had spontaneous virologic clearance. Early therapy with pegylated interferon was initiated for 5 patients with persistent viremia and led to a sustained virologic response in 2 individuals. All patients agreed to undergo human immunodeficiency virus counseling and testing, as well as to receive immunization for hepatitis A and B. CONCLUSIONS Incarceration presents a unique opportunity to identify injection drug users with acute HCV infection, to initiate counseling regarding other bloodborne pathogens, and to facilitate immunizations and HCV treatment.
Collapse
Affiliation(s)
- Barbara H McGovern
- Lemuel Shattuck Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Kiyohara C, Yoshimasu K, Takayama K, Nakanishi Y. EPHX1 polymorphisms and the risk of lung cancer: a HuGE review. Epidemiology 2006; 17:89-99. [PMID: 16357600 DOI: 10.1097/01.ede.0000187627.70026.23] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Microsomal epoxide hydrolase 1 (EPHX1) plays an important role in both the activation and detoxification of tobacco-derived carcinogens. Polymorphisms at exons 3 and 4 of the EPHX1 gene have been reported to be associated with variations in EPHX1 activity. The aim of this study is to review and summarize the available molecular epidemiologic studies of lung cancer and EPHX1. METHODS We searched MEDLINE, Current Contents, and Web of Science databases for studies published before August 2004. We conducted a systematic review and meta-analysis of 13 case-control studies. Summary odds ratios and summary prevalence of the variant allele (genotype) of both polymorphisms in the EPHX1 gene were calculated using the DerSimonian and Laird method. RESULTS The low-activity (variant) genotype of EPHX1 polymorphism at exon 3 was associated with decreased risk of lung cancer (odds ratio = 0.65; 95% confidence interval = 0.44-0.96) in lung cancer risk among whites. In white populations, the high-activity (variant) genotype of EPHX1 polymorphism at exon 4 was associated with a modest increase in risk of lung cancer (1.22; 0.79-1.90) and the predicted low activity was associated with a modest decrease in risk (0.72; 0.43-1.22). CONCLUSIONS EPHX1 enzyme may act as a phase I enzyme in lung carcinogenesis. The low-activity genotype of EPHX1 gene is associated with decreased risk of lung cancer among whites.
Collapse
Affiliation(s)
- Chikako Kiyohara
- Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | | | | | | |
Collapse
|
|
31
|
Abstract
Hepatitis C follows a variable course with some patients developing progressive liver fibrosis, cirrhosis and hepatocellular carcinoma, while others have minimal or no significant liver disease after decades of infection. Studies have identified both host and viral factors associated with disease progression. The importance of general factors such as age at infection, gender, immune status and alcohol consumption has long been recognized; however recently, polymorphisms in a wide array of genes have also been shown to be associated with progressive fibrosis. How specific viral proteins may contribute to disease progression has also been studied. This review highlights what is currently known about the factors associated with progressive liver injury in patients with hepatitis C. A greater understanding of the determinants of disease progression will hopefully lead to improved utilization of existing treatments and ultimately may aid in identification of new therapeutic targets.
Collapse
Affiliation(s)
- Jordan J Feld
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | | |
Collapse
|
|
32
|
Kato N, Ji G, Wang Y, Baba M, Hoshida Y, Otsuka M, Taniguchi H, Moriyama M, Dharel N, Goto T, Shao RX, Matsuura T, Ishii K, Shiina S, Kawabe T, Muramatsu M, Omata M. Large-scale search of single nucleotide polymorphisms for hepatocellular carcinoma susceptibility genes in patients with hepatitis C. Hepatology 2005; 42:846-853. [PMID: 16175604 DOI: 10.1002/hep.20860] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Hepatitis C virus (HCV) infection is a major risk factor for developing hepatocellular carcinoma (HCC). The host genetic factors that are involved in the development of HCC in patients with HCV infection remain to be investigated. To search for single nucleotide polymorphisms (SNPs) in HCC susceptibility genes, 393 SNPs in 171 candidate genes were examined in 188 Japanese patients with chronic HCV infection, including 77 patients with HCC. HCC-related SNPs were then examined in another 188 patients (including 93 patients with HCC) with chronic HCV infection. Haplotype analyses of HCC-related genes were performed in a total of 376 patients. Of the 393 SNPs, 31 SNPs in 29 genes were significantly associated with HCC based on an initial screening (P < .05). Of these 31 SNPs, 3 SNPs of 3 genes (SCYB14, GFRA1, and CRHR2) were significantly associated with HCC in a secondary screening. Haplotype analyses of these 3 genes identified 2 haplotype blocks associated with HCC. In conclusion, these SNPs and haplotypes located in the SCBY14, CRHR2, and GFRA1 genes will be used as markers to identify a subgroup of Japanese patients with chronic HCV infection who are at high risk of developing HCC.
Collapse
Affiliation(s)
- Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Feo F, De Miglio MR, Simile MM, Muroni MR, Calvisi DF, Frau M, Pascale RM. Hepatocellular carcinoma as a complex polygenic disease. Interpretive analysis of recent developments on genetic predisposition. Biochim Biophys Acta Rev Cancer 2005; 1765:126-47. [PMID: 16216419 DOI: 10.1016/j.bbcan.2005.08.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2005] [Revised: 08/25/2005] [Accepted: 08/26/2005] [Indexed: 01/11/2023]
Abstract
The different frequency of hepatocellular carcinoma (HCC) in humans at risk suggests a polygenic predisposition. However, detection of genetic variants is difficult in genetically heterogeneous human population. Studies on mouse and rat models identified 7 hepatocarcinogenesis susceptibility (Hcs) and 2 resistance (Hcr) loci in mice, and 7 Hcs and 9 Hcr loci in rats, controlling multiplicity and size of neoplastic liver lesions. Six liver neoplastic nodule remodeling (Lnnr) loci control number and volume of re-differentiating lesions in rat. A Hcs locus, with high phenotypic effects, and various epistatic gene-gene interactions were identified in rats, suggesting a genetic model of predisposition to hepatocarcinogenesis with different subset of low-penetrance genes, at play in different subsets of population, and a major locus. This model is in keeping with human HCC epidemiology. Several putative modifier genes in rodents, deregulated in HCC, are located in chromosomal segments syntenic to sites of chromosomal aberrations in humans, suggesting possible location of predisposing loci. Resistance to HCC is associated with lower genomic instability and downregulation of cell cycle key genes in preneoplastic and neoplastic lesions. p16(INK4A) upregulation occurs in susceptible and resistant rat lesions. p16(INK4A)-induced growth restraint was circumvented by Hsp90/Cdc37 chaperons and E2f4 nuclear export by Crm1 in susceptible, but not in resistant rats and human HCCs with better prognosis. Thus, protective mechanisms seem to be modulated by HCC modifiers, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.
Collapse
Affiliation(s)
- F Feo
- Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, Via P. Manzella 4, 07100 Sasssari, Italy.
| | | | | | | | | | | | | |
Collapse
|
|
34
|
Kirk GD, Turner PC, Gong Y, Lesi OA, Mendy M, Goedert JJ, Hall AJ, Whittle H, Hainaut P, Montesano R, Wild CP. Hepatocellular carcinoma and polymorphisms in carcinogen-metabolizing and DNA repair enzymes in a population with aflatoxin exposure and hepatitis B virus endemicity. Cancer Epidemiol Biomarkers Prev 2005; 14:373-9. [PMID: 15734960 DOI: 10.1158/1055-9965.epi-04-0161] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
High rates of hepatocellular carcinoma (HCC) in The Gambia, West Africa, are primarily due to a high prevalence of chronic hepatitis B virus infection and heavy aflatoxin exposure via groundnut consumption. We investigated genetic polymorphisms in carcinogen-metabolizing (GSTM1, GSTT1, HYL1*2) and DNA repair (XRCC1) enzymes in a hospital-based case-control study. Incident HCC cases (n = 216) were compared with frequency-matched controls (n = 408) with no clinically apparent liver disease. Although the prevalence of variant genotypes was generally low, in multivariable analysis (adjusting for demographic factors, hepatitis B virus, hepatitis C virus, and TP53 status), the GSTM1-null genotype [odds ratio (OR), 2.45; 95% confidence interval (95% CI), 1.21-4.95] and the heterozygote XRCC1-399 AG genotype (OR, 3.18; 95% CI, 1.35-7.51) were significantly associated with HCC. A weak association of the HYL1*2 polymorphism with HCC was observed but did not reach statistical significance. GSTT1 was not associated with HCC. The risk for HCC with null GSTM1 was most prominent among those with the highest groundnut consumption (OR, 4.67; 95% CI, 1.45-15.1) and was not evident among those with less than the mean groundnut intake (OR, 0.64; 95% CI, 0.20-2.02). Among participants who had all three suspected aflatoxin-related high-risk genotypes [GSTM1 null, HLY1*2 (HY/HH), and XRCC1 (AG/GG)], a significant 15-fold increased risk of HCC was observed albeit with imprecise estimates (OR, 14.7; 95% CI, 1.27-169). Our findings suggest that genetic modulation of carcinogen metabolism and DNA repair can alter susceptibility to HCC and that these effects may be modified by environmental factors.
Collapse
Affiliation(s)
- Gregory D Kirk
- Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH/Department of Health and Human Services, Bethesda, MD 20892, USA.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Blake MJ, Castro L, Leeder JS, Kearns GL. Ontogeny of drug metabolizing enzymes in the neonate. Semin Fetal Neonatal Med 2005; 10:123-38. [PMID: 15701578 DOI: 10.1016/j.siny.2004.11.001] [Citation(s) in RCA: 120] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Fetal exposure to xenobiotics is modulated to a considerable degree by the metabolic capabilities of the mother and the placenta. However, once liberated from the uterine environment the neonate is instantly exposed to a wide array of new macromolecules in the form of byproducts of cellular metabolism, dietary constituents, environmental toxins and pharmacologic agents. The rapid and efficient biotransformation of these compounds by Phase I and Phase II drug-metabolizing enzymes is an essential process if the infant is to avoid the accumulation of reactive compounds that could produce cellular injury or tissue dysfunction. Genetic polymorphisms and environmental factors are known to contribute dramatically to individual variation in the activity of drug-metabolizing enzymes. More recently, it has become apparent that programmed, developmental, regulatory events occur - independent of genotype - which further add to individual variation in drug metabolism. An appreciation of the impact of ontogeny on the expression and functional activity of the major drug-metabolizing enzymes enables the practicing clinician to predict the ultimate consequence of drug administration in the neonate to help guide optimal drug therapy.
Collapse
Affiliation(s)
- Michael J Blake
- Department of Pediatrics, University of Missouri - Kansas City, Division of Pediatric Pharmacology and Medical Toxicology, The Children's Mercy Hospitals and Clinics, 2401 Gillham Road, Kansas City, MO 64108, USA
| | | | | | | |
Collapse
|
|
36
|
Wang Y, Zhang J, Liu CL, Gu X, Zhang XM. Nano-flow multidimensional liquid chromatography with electrospray ionization time-of-flight mass spectrometry for proteome analysis of hepatocellular carcinoma. Anal Chim Acta 2005. [DOI: 10.1016/j.aca.2004.09.036] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
|
|
37
|
Abstract
In addition to viral and environmental/behavioural factors, host genetic diversity is believed to contribute to the spectrum of clinical outcomes in hepatitis C virus (HCV) infection. This paper reviews the literature with respect to studies of host genetic determinants of HCV outcome and attempts to highlight trends and synthesise findings. With respect to the susceptibility to HCV infection, several studies have replicated associations of the HLA class II alleles DQB1(*)0301 and DRB1(*)11 with self-limiting infection predominantly in Caucasian populations. Meta-analyses yielded summary estimates of 3.0 (95% CI: 1.8-4.8) and 2.5 (95% CI: 1.7-3.7) for the effects of DQB1(*)0301 and DRB1(*)11 on self-limiting HCV, respectively. Studies of genetics and the response to interferon-based therapies have largely concerned single-nucleotide polymorphisms and have been inconsistent. Regarding studies of genetics and the progression of HCV-related disease, there is a trend with DRB1(*)11 alleles and less severe disease. Studies of extrahepatic manifestations of chronic HCV have shown an association between DQB1(*)11 and DR3 with the formation of cryoglobulins. Some important initial observations have been made with respect to genetic determinants of HCV outcome. Replication studies are needed for many of these associations, as well as biological data on the function of many of these polymorphisms.
Collapse
Affiliation(s)
- L J Yee
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| |
Collapse
|
|
38
|
Zhu ZZ, Cong WM, Liu SF, Dong H, Zhu GS, Wu MC. Homozygosity for Pro of p53 Arg72Pro as a potential risk factor for hepatocellular carcinoma in Chinese population. World J Gastroenterol 2005; 11:289-92. [PMID: 15633234 PMCID: PMC4205420 DOI: 10.3748/wjg.v11.i2.289] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Codon 72 exon 4 polymorphism (Arg72Pro) of the p53 gene has been implicated in cancer risk. Our objective was to investigate the possible association between p53 Arg72Pro polymorphism and susceptibility to hepatocellular carcinoma (HCC) among Chinese population.
METHODS: The p53 Arg72Pro genotypes were determined by PCR-based restriction fragment length polymorphism (RFLP) analysis in 507 HCC cases and 541 controls. Odds ratios (ORs) for HCC and 95% confidence intervals (CIs) from unconditional logistic regression models were used to evaluate relative risks. Potential risk factors were included in the logistic regression models as covariates in the multivariate analyses on genotype and HCC.
RESULTS: The frequencies for Pro and Arg alleles were 44.5%, 55.5% in HCC cases, and 40.3% and 59.7% in controls, respectively. The Pro allele was significantly associated with the presence of HCC (P = 0.05) and had a higher risk for HCC (OR = 1.19, 95% CI 1.00-1.41) as compared with the Arg allele. After adjusted for potential risk factors, Arg/Pro heterozygotes had an 1.21-fold increased risk (95% CI 0.82-1.78, P = 0.34) of HCC compared with Arg homozygotes, whereas the risk for Pro homozygotes was 1.79 (95% CI 1.06-3.01, P = 0.03) times higher than that for Arg homozygotes. Pro-allele carriers had a higher relative risk of HCC than the Arg-only carriers (adjusted OR = 1.33, 95% CI 0.92-1.92, P = 0.13), although the difference was not statistically significant.
CONCLUSION: Homozygosity for Pro of p53 Arg72Pro is potentially one of the genetic risk factors for HCC in Chinese population. The p53 Arg72Pro polymorphism may be used as a stratification marker in screening individuals at a high risk of HCC.
Collapse
Affiliation(s)
- Zhong-Zheng Zhu
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | | | | | | | | | | |
Collapse
|
|
39
|
Tsai JF, Jeng JE, Chuang LY, Ho MS, Ko YC, Lin ZY, Hsieh MY, Chen SC, Chuang WL, Wang LY, Yu ML, Dai CY. Habitual betel quid chewing and risk for hepatocellular carcinoma complicating cirrhosis. Medicine (Baltimore) 2004; 83:176-187. [PMID: 15118544 DOI: 10.1097/01.md.0000126971.80227.a4] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
This case-control study aimed to assess the independent and interactive role of habitual betel quid chewing and known risk factors for hepatocellular carcinoma (HCC). Subjects enrolled included 210 pairs of sex- and age-matched cirrhotic patients with HCC, patients with cirrhosis alone, and healthy controls. Information on risk factors was obtained through serologic examination of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV), and a standardized personal interview with a structured questionnaire. Multivariate analysis indicated that betel quid chewing (odds ratio [OR], 5.81; 95% confidence interval [CI], 2.26-14.94); HBsAg (OR, 37.98; 95% CI, 19.65-73.42); and anti-HCV (OR, 47.23; 95% CI, 18.86-118.25) were independent risk factors for HCC when HCC patients were compared with healthy controls. Using patients with cirrhosis alone as a reference group, multivariate analysis indicated that only betel quid chewing (OR, 1.69; 95% CI, 1.04-2.76) and HBsAg (OR, 1.54; 95% CI, l.01-2.37) were independent risk factors for HCC. There was an additive interaction between betel quid chewing and the presence of either HBsAg (synergy index, 5.22) or anti-HCV (synergy index, 1.35). Moreover, a higher risk of HCC was associated with a longer duration of betel quid chewing and a larger amount of betel quid consumed (each p(for trend) < 0.0001). In conclusion, betel quid chewing is an independent risk factor for cirrhotic HCC. There is an additive interaction between betel quid chewing and chronic hepatitis B and/or hepatitis C virus infection.
Collapse
Affiliation(s)
- Jung-Fa Tsai
- From the Department of Internal Medicine, Clinical Laboratory, Biochemistry, and Public Health, Kaohsiung Medical University College of Medicine; the National Health Research Institutes, and the Institute of Biomedical Sciences, Academia Sinica, Taiwan
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Wang Y, Kato N, Hoshida Y, Otsuka M, Taniguchi H, Moriyama M, Shiina S, Kawabe T, Ito YM, Omata M. UDP-glucuronosyltransferase 1A7 genetic polymorphisms are associated with hepatocellular carcinoma in japanese patients with hepatitis C virus infection. Clin Cancer Res 2004; 10:2441-2446. [PMID: 15073122 DOI: 10.1158/1078-0432.ccr-1187-3] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Genetic polymorphisms of UDP-glucuronosyltransferase 1A7 (UGT1A7), which detoxifies endogenous and environmental carcinogens, have been reported to be associated with hepatocellular carcinoma (HCC) in German populations. On the other hand, we reported that interleukin-1 beta (IL-1 beta) gene polymorphisms were associated with hepatitis C virus (HCV)-related HCC. In this study, we evaluated the association of both genes with the risk of HCC in Japanese HCV-infected patients. EXPERIMENTAL DESIGN Genetic polymorphisms of UGT1A7 and IL-1 beta were investigated in 280 Japanese patients (122 with HCC and 158 without HCC) with chronic HCV infections, by use of standard PCR-based genotyping techniques. RESULTS We designated the UGT1A7*1 allele (a haplotype conferring higher activity) as H and the *2, *3, and *4 alleles (haplotypes conferring lower activity) as L. The proportions of UGT1A7 L/L and H/L alleles (genotypes) in patients with HCC (25% and 45%, respectively) were higher than those in patients without HCC (15% and 39%, respectively) with odds ratios of 2.73 (95% confidence interval, 1.40-5.35) and 1.80 (95% confidence interval, 1.05-3.09), respectively, compared with the UGT1A7 H/H alleles. Multivariate analyses revealed that UGT1A7 L/L and IL-1 beta/-31T/T-511C/C genotypes, the presence of cirrhosis, age >60 years, male sex, and alpha-fetoprotein >20 microg/ml were associated with the presence of HCC (odds ratios, 2.33, 2.67, 4.20, 3.12, 3.09, and 2.90, respectively). CONCLUSION The UGT1A7 polymorphisms together with IL-1 beta were associated with the presence of HCC in Japanese HCV-infected patients.
Collapse
Affiliation(s)
- Yue Wang
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Alter MJ. Reply. Clin Infect Dis 2003. [DOI: 10.1086/379832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
|
|
42
|
Rossi L, Leveri M, Gritti C, De Silvestri A, Zavaglia C, Sonzogni L, Silvestri L, Civardi E, Mondelli MU, Silini EM. Genetic polymorphisms of steroid hormone metabolizing enzymes and risk of liver cancer in hepatitis C-infected patients. J Hepatol 2003; 39:564-70. [PMID: 12971967 DOI: 10.1016/s0168-8278(03)00355-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND/AIMS Genetic polymorphisms of enzymes involved in hormone metabolism can influence hormonal activities and risk of hormone-dependent cancers. As progression of chronic hepatitis C and risk of liver cancer is higher in males than in females, we evaluated whether the polymorphisms of three enzymes participating in the pathway of estrogen and androgen biosynthesis and inactivation, 5alpha-reductase type II (SRD5A2), cytochrome P450c17alpha (CYP17) and catechol-O-methyltransferase (COMT), might affect the expression of hepatitis C virus (HCV)-related liver disease. METHODS The study included 78 healthy subjects and 387 HCV patients: 100 asymptomatic carriers, 105 hepatitis, 90 cirrhosis and 92 hepatocellular carcinomas (HCC). Variant positions SRD5A2 V89L and A49T, CYP17 (-34)T/C and COMT V108M were analysed by polymerase chain reaction and restriction fragment length polymorphism. A cross-sectional study of association was performed, considering carriers as reference category. RESULTS The CYP17 (-34)C/C genotype was over-represented in HCC patients as compared to carriers (22.5 vs. 11.2%, odds ratio (OR): 2.29, P: 0.05). Females mostly contributed to this association (OR: 4.95, P: 0.01) and OR values increased in post-menopausal women (OR: 6.00, P: 0.03). No differences were observed for SRD5A2 and COMT gene polymorphisms. CONCLUSIONS CYP17 high-activity alleles associated with increased circulating levels of estrogens and androgens may affect liver cancer risk in HCV-infected women.
Collapse
Affiliation(s)
- Laura Rossi
- ASAEV, Via Garibaldi 13, 24040 Bonate Sotto (BG), Italy.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Mühlbauer M, Bosserhoff AK, Hartmann A, Thasler WE, Weiss TS, Herfarth H, Lock G, Schölmerich J, Hellerbrand C. A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease. Gastroenterology 2003; 125:1085-93. [PMID: 14517792 DOI: 10.1016/s0016-5085(03)01213-7] [Citation(s) in RCA: 163] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Factors influencing the progression of chronic hepatitis C virus (HCV) infection are poorly understood. Monocyte chemotactic protein-1 (MCP-1) is a potent chemokine, and its hepatic expression is up-regulated during chronic HCV infection mainly in activated hepatic stellate cells (HSC). In this study, we investigated the correlation of the functional -2518 MCP-1 promoter polymorphism with hepatic MCP-1 expression and the disease outcome in patients with HCV. METHODS MCP-1 genotyping was performed in 206 patients and 139 healthy controls. Hepatic MCP-1 messenger RNA (mRNA) expression was quantified by real-time PCR in 58 HCV patients. Cytokine-induced MCP-1 secretion of activated human HSC (n = 13) was determined by enzyme-linked immunosorbent assay (ELISA). Mobility-shift assays were performed using probes corresponding to the MCP-1 promoter sequence (-2511 to -2528) with or without the A to G mutation at -2518. RESULTS Frequency of MCP-1 genotypes did not differ between HCV patients and controls. However, carriers of the G allele were significantly more frequent in HCV patients with more advanced fibrosis and severe inflammation. In accordance, hepatic MCP-1 mRNA levels were significantly higher in patients with more advanced fibrosis and in patients carrying the G allele. Furthermore, cytokine-induced MCP-1 secretion of HSC isolated from carriers of the G allele was significantly higher, and there was binding activity in nuclear extracts from activated HSC specifically to the G allele, providing a potential mechanism for the differences seen. CONCLUSIONS Inheritance of the -2518 MCP-1 G allele, which appears to affect hepatic MCP-1 expression, may predispose HCV patients to more severe hepatic inflammation and fibrosis.
Collapse
Affiliation(s)
- Marcus Mühlbauer
- Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Kim SK, Woodcroft KJ, Kim SG, Novak RF. Insulin and glucagon signaling in regulation of microsomal epoxide hydrolase expression in primary cultured rat hepatocytes. Drug Metab Dispos 2003; 31:1260-8. [PMID: 12975336 DOI: 10.1124/dmd.31.10.1260] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Microsomal epoxide hydrolase (mEH) plays an important role in the detoxification of a broad range of epoxide intermediates and has been reported to be decreased during diabetes and fasting. The signaling pathways involved in the regulation of mEH expression in response to insulin and glucagon were examined in primary cultured rat hepatocytes. mEH protein levels were increased 2- to 6-fold in hepatocytes cultured for 1 to 4 days, respectively, in the presence of insulin. Concentration-response studies revealed that insulin concentrations >or=1 nM resulted in increased mEH protein levels. The phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin or LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one], and rapamycin, an inhibitor of p70 S6 kinase phosphorylation, ameliorated the insulin-mediated increase in mEH protein levels. The p38 mitogen-activated protein (MAP) kinase inhibitors SB203580 and SB202190 also abrogated the insulin-mediated increase in mEH protein. Treatment of cells with glucagon, 8-bromo-cAMP, or dibutyryl-cAMP for 3 days resulted in decreased mEH protein levels. Pretreatment with the protein kinase A (PKA) inhibitor H89 (N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline) prior to glucagon addition markedly attenuated the glucagon effect, implicating PKA signaling in the regulation of mEH expression. These data demonstrate that insulin and glucagon regulate, in an opposing manner, the expression of mEH in primary cultured rat hepatocytes. Furthermore, these data suggest that PI3K and p70 S6 kinase are active in the regulation of insulin-mediated mEH expression. We also provide data implicating p38 MAP kinase in the insulin-mediated increase in mEH levels. Moreover, cAMP and PKA are implicated in mediating the inhibitory effect of glucagon on mEH expression.
Collapse
Affiliation(s)
- Sang K Kim
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | | | | | | |
Collapse
|
|
45
|
Somech R, Amariglio N, Spirer Z, Rechavi G. Genetic predisposition to infectious pathogens: a review of less familiar variants. Pediatr Infect Dis J 2003; 22:457-61. [PMID: 12792391 DOI: 10.1097/01.inf.0000068205.82627.55] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The susceptibility and clinical manifestations of infectious diseases in human populations are influenced by a variety of factors, among them host genetics. Obvious examples for the effect of host genetics on predisposition to unique infections are the primary immunodeficiency diseases. Minor gene variants that influence the host immune system are much more common. The iceberg model can be used to illustrate the epidemiology of immunodeficiency states. Accordingly only a few individuals have known and severe recognized primary immunodeficiencies, whereas many more patients have mild immunodeficiencies that may remain undiagnosed and are predisposed to a unique infectious disease. We review some of the less common variants that influence the host defense and predispose to certain infectious agents or change their outcome.
Collapse
Affiliation(s)
- Raz Somech
- Pediatric Hemato-Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | | | | | | |
Collapse
|
|
46
|
Silvestri L, Sonzogni L, De Silvestri A, Gritti C, Foti L, Zavaglia C, Leveri M, Cividini A, Mondelli MU, Civardi E, Silini EM. CYP enzyme polymorphisms and susceptibility to HCV-related chronic liver disease and liver cancer. Int J Cancer 2003; 104:310-7. [PMID: 12569554 DOI: 10.1002/ijc.10937] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Cancer risk can be influenced by the exposure to endogenous or environmental toxins. Polymorphic enzymes involved in the metabolic activation/detoxification of carcinogens may account for individual variations of risk. We studied the polymorphisms of five enzymes of the P450 superfamily, CYP1A1, CYP1A2, CYP2D6, CYP2E1 and CY3A4, as risk factors for liver disease progression and cancer in hepatitis C virus-infected patients. CYP genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism or allele-specific PCR. Different stages of disease were considered, as follows: 90 asymptomatic carriers and 87 chronic hepatitis, 92 cirrhosis and 91 hepatocellular carcinoma (HCC) cases. Reference allele frequencies were obtained from 99 blood donors. Allele distributions among categories were compared using the chi(2) test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to express relative risks. Independent associations were modeled by correspondence analysis and logistic regression. Frequencies of the CYP1A1 highly inducible alleles, MspI m2 and Val, were increased in liver disease patients compared with carriers; no specific association with HCC was found. The high-activity CYP2E1 c2 allele was underrepresented among HCC patients with respect to other HCV categories, including cirrhosis. CYP2D6 poor metabolizer (PM) genotypes were significantly more frequent in healthy subjects (7.1%) and carriers (11.1%) than in hepatitis/cirrhosis (4.6%) and HCC (1.2%) patients. This was confirmed by multivariable analysis. PM genotypes protected against progressive disease as ORs reduced proportionally to stage. The age at diagnosis for HCC was anticipated in non-PM individuals. No differences were seen for CYP1A2 and CYP3A4 genes. Polymorphic variants of CYP genes may contribute to the progression of liver disease and HCC risk in HCV-infected subjects.
Collapse
Affiliation(s)
- Laura Silvestri
- Associazione Studi Avanzati Epatiti Virali, Bonate Sotto (BG), Italy
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Bataller R, North KE, Brenner DA. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology 2003; 37:493-503. [PMID: 12601343 DOI: 10.1053/jhep.2003.50127] [Citation(s) in RCA: 264] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Liver fibrosis is a highly dynamic process in which multiple genes interact with environmental factors. Recent human epidemiologic studies have identified possible polymorphisms in a number of candidate genes that influence the progression of liver fibrosis. These genetic factors could explain the broad spectrum of responses to the same etiologic agent found in patients with chronic liver diseases. Polymorphisms in genes encoding immunoregulatory proteins, proinflammatory cytokines, and fibrogenic factors may influence disease progression in patients with alcohol-induced liver disease, primary biliary cirrhosis, or chronic hepatitis C. However, some of the studies have yielded contradictory results. For example, conflicting results have been obtained in studies assessing the role of mutations in the hemochromatosis gene on fibrosis progression in patients with chronic hepatitis C. Large-scale, well-designed studies are required to clarify the actual role of this factor and other genetic variants in liver fibrosis.
Collapse
Affiliation(s)
- Ramón Bataller
- Department of Medicine, Biochemistry and Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599, USA
| | | | | |
Collapse
|