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Zhang D, Shen Q, Li XF. Evaluating Powdered Activated Carbon for Adsorption of Nitrogenous Organics in Water Using HDPairFinder. ACS ENVIRONMENTAL AU 2025; 5:308-318. [PMID: 40416845 PMCID: PMC12100545 DOI: 10.1021/acsenvironau.4c00133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 01/31/2025] [Accepted: 02/04/2025] [Indexed: 05/27/2025]
Abstract
Amino-containing compounds are key precursors to highly toxic nitrogenous disinfection byproducts (DBPs) and odorous DBPs, posing a critical challenge for drinking water utilities. This study systematically evaluated the adsorption performance of six commercial powdered activated carbons (PACs) for removing soluble amino-containing compounds using amino acids as model compounds. Among them, PHF and AN PAC demonstrated superior removal efficiencies for six tested amino acids, ranging from 77 to 98% for PHF PAC and 83 to 96% for AN PAC. Subsequent analysis focused on PHF, AN, and HB PACs to investigate adsorption kinetics and effects of water parameters, including initial amino acid concentration, pH, and natural organic matter (NOM) on removal efficiencies. Optimal removal efficiencies were observed for PHF and AN PACs at pH levels between 6 and 8, while increased NOM levels significantly reduced amino acid adsorption. Finally, a hydrogen/deuterium isotopic labeling-based nontargeted analysis was applied to evaluate the removal of amino-containing compounds from source water (represented by Suwannee River standard reference materials). PHF exhibited the highest removal efficiency, achieving a 47% reduction in the total ion chromatogram (TIC) intensity of labeled amino-containing features, followed by AN at 21% and HB at 19%. The decrease in the TIC intensity and number of labeled amino-containing features aligned with the trends observed in adsorption, establishes a consistent ranking of PHF > AN > HB PAC. PAC can be seamlessly integrated into existing drinking water treatment processes and applied on an as-needed basis. Our results could provide valuable guidance for its effective application in water treatment plants.
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Affiliation(s)
- Di Zhang
- Division of Analytical and
Environmental Toxicology, Department of Laboratory Medicine and Pathology,
Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, AlbertaT6G 2G3, Canada
| | - Qiming Shen
- Division of Analytical and
Environmental Toxicology, Department of Laboratory Medicine and Pathology,
Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, AlbertaT6G 2G3, Canada
| | - Xing-Fang Li
- Division of Analytical and
Environmental Toxicology, Department of Laboratory Medicine and Pathology,
Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, AlbertaT6G 2G3, Canada
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Marlés-Torres A, Bessa-Jambrina S, Galán-Rodríguez C. Ultra-High-Performance Liquid Chromatography Combined With Mass Spectrometry Detection Analytical Method for the Determination of N-Nitrosoduloxetine in Duloxetine HCl. Biomed Chromatogr 2025; 39:e6084. [PMID: 39916635 DOI: 10.1002/bmc.6084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/21/2024] [Accepted: 11/27/2024] [Indexed: 05/08/2025]
Abstract
In the present study, one simple, fast, feasible, and sensitive ultra-high-performance liquid chromatography combined with mass spectrometry detection method, using electrospray ionization, is proposed. This method was developed and validated for the determination of N-nitrosoduloxetine content in Duloxetine HCl active pharmaceutical ingredient in 11 min employing a simple preparation method for both reference and sample solutions. The proposed method was validated as per regulatory guidelines. Acquity HSS T3 (3.0 × 100 mm, 1.8 μm) column and formic acid 0.1% in water combined with acetonitrile were used for chromatographic separation. The limit of detection and the limit of quantification-reporting threshold-were found to be 0.7 and 70 ppb, respectively. The trueness and precision of the method have been demonstrated in the working range, giving values of recovery within the range of 100%-110%, and the regression coefficients (R) were found to be in the range of 0.9990-0.9991. This method could be used for controlling N-nitrosoduloxetine content in duloxetine HCl drug substance batches manufactured at Moehs group.
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Affiliation(s)
- Anna Marlés-Torres
- Research and Development Department, Polígono Industrial Cova-Solera, Moehs Ibérica, Rubí, Barcelona, Spain
| | - Sergio Bessa-Jambrina
- Research and Development Department, Polígono Industrial Cova-Solera, Moehs Ibérica, Rubí, Barcelona, Spain
| | - Cristóbal Galán-Rodríguez
- Research and Development Department, Polígono Industrial Cova-Solera, Moehs Ibérica, Rubí, Barcelona, Spain
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Lu X, Lin W, Zheng J, Huang W, Yu S, Chen H, Wang H, Zhang Y. Sodium nitrite orchestrates macrophage mimicry of tongue squamous carcinoma cells to drive lymphatic metastasis. Br J Cancer 2025; 132:340-353. [PMID: 39799274 PMCID: PMC11833070 DOI: 10.1038/s41416-024-02923-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 11/21/2024] [Accepted: 11/28/2024] [Indexed: 01/15/2025] Open
Abstract
BACKGROUND Tongue squamous cell carcinoma (TSCC) is a malignant oral cancer with unclear pathogenesis that shows a tendency for early-stage lymphatic metastasis. This results in a poor prognosis, with a low 5-year survival rate. Dietary sodium nitrite (NaNO2) has proposed associations with disease, including cancer. However, a direct relationship between NaNO2 and TSCC has not been established. METHODS In vitro and in vivo assays were used to investigate the role of NaNO2 in TSCC. Protein expression in TSCC specimens was detected by immunohistochemistry and immunofluorescence. The molecular mechanism was determined using RT-qPCR, western blot, RNA-seq, luciferase reporter assays, migration assays, and FACS analysis. More detail of methods can be found in the Materials and methods section. RESULTS The data in this study showed that NaNO2 did not initiate carcinogenesis in the tongue but improved the lymphatic metastatic potential of TSCC cells in the specified experimental period. During metastasis to lymph nodes, monocyte-macrophage markers were upregulated in TSCC cells, whereas keratin markers were downregulated. Specifically, expression of the CD68 gene was high in TSCC cells following NaNO2-induced TSCC phenotypic switching. These phenotypic changes were associated with activation of transcription factor cyclic-AMP response binding protein (CREB1), which directly targets CD68 transcription. Furthermore, blocking CREB1 activity either through gene knockout or specific inhibitor treatment decreased the migration ability of TSCC cells and suppressed CD68 expression. CONCLUSIONS Our findings highlight the role of NaNO2 in enabling macrophage mimicry in TSCC cells through the CREB1-CD68 signaling pathway, which promotes lymphatic metastasis. Shedding light on drivers of lymphatic metastasis in TSCC and providing a new perspective on dietary strategies to improve outcomes of patients with TSCC.
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Affiliation(s)
- Xiangwan Lu
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Weifan Lin
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Junheng Zheng
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Wuheng Huang
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Shuyi Yu
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Haoxiang Chen
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, PR China
| | - Hua Wang
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, PR China.
| | - Yan Zhang
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, PR China.
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Heflich RH, Bishop ME, Mittelstaedt RA, Yan J, Guerrero SK, Sims AM, Mitchell K, Moore N, Li X, Mei N, Elespuru RK, King ST, Keire DA, Kruhlak NL, Dorsam RT, Raw AS, Davis Bruno KL, McGovern TJ, Atrakchi AH. Optimizing the detection of N-nitrosamine mutagenicity in the Ames test. Regul Toxicol Pharmacol 2024; 153:105709. [PMID: 39343352 DOI: 10.1016/j.yrtph.2024.105709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 09/23/2024] [Accepted: 09/25/2024] [Indexed: 10/01/2024]
Abstract
Accurately determining the mutagenicity of small-molecule N-nitrosamine drug impurities and nitrosamine drug substance-related impurities (NDSRIs) is critical to identifying mutagenic and cancer hazards. In the current study we have evaluated several approaches for enhancing assay sensitivity for evaluating the mutagenicity of N-nitrosamines in the bacterial reverse mutagenicity (Ames) test. Preincubation assays were conducted using five activation conditions: no exogenous metabolic activation and metabolic activation mixes employing both 10% and 30% liver S9 from hamsters and rats pretreated with inducers of enzymatic activity. In addition, preincubations were conducted for both 60 min and 30 min. These test variables were evaluated by testing 12 small-molecule N-nitrosamines and 17 NDSRIs for mutagenicity in Salmonella typhimurium tester strains TA98, TA100, TA1535, and TA1537, and Escherichia coli strain WP2 uvrA (pKM101). Eighteen of the 29 N-nitrosamine test substances tested positive under one or more of the testing conditions and all 18 positives could be detected by using tester strains TA1535 and WP2 uvrA (pKM101), preincubations of 30 min, and S9 mixes containing 30% hamster liver S9. In general, the conditions under which NDSRIs were mutagenic were similar to those found for small-molecule N-nitrosamines.
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Affiliation(s)
- Robert H Heflich
- U.S. Food and Drug Administration, National Center for Toxicological Research, USA.
| | - Michelle E Bishop
- U.S. Food and Drug Administration, National Center for Toxicological Research, USA
| | | | - Jian Yan
- U.S. Food and Drug Administration, National Center for Toxicological Research, USA
| | - Sharon K Guerrero
- U.S. Food and Drug Administration, National Center for Toxicological Research, USA
| | - Audrey M Sims
- U.S. Food and Drug Administration, National Center for Toxicological Research, USA
| | - Kamela Mitchell
- U.S. Food and Drug Administration, National Center for Toxicological Research, USA
| | - Nyosha Moore
- U.S. Food and Drug Administration, National Center for Toxicological Research, USA
| | - Xilin Li
- U.S. Food and Drug Administration, National Center for Toxicological Research, USA
| | - Nan Mei
- U.S. Food and Drug Administration, National Center for Toxicological Research, USA
| | | | - Sruthi T King
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, USA
| | - David A Keire
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, USA
| | - Naomi L Kruhlak
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Translational Sciences, USA
| | - Robert T Dorsam
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, USA
| | - Andre S Raw
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, USA
| | - Karen L Davis Bruno
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of New Drugs, USA
| | - Timothy J McGovern
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of New Drugs, USA
| | - Aisar H Atrakchi
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of New Drugs, USA
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Clemmensen PJ, Brix N, Schullehner J, Toft G, Søgaard Tøttenborg S, Sørig Hougaard K, Bjerregaard AA, Halldorsson TI, Olsen SF, Hansen B, Stayner LT, Sigsgaard T, Kolstad H, Bonde JPE, Ramlau-Hansen CH. Maternal use of nitrosatable drugs during pregnancy and adult male reproductive health: A population-based cohort study. Andrology 2024; 12:1740-1750. [PMID: 38488298 DOI: 10.1111/andr.13625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 01/30/2024] [Accepted: 02/19/2024] [Indexed: 11/08/2024]
Abstract
BACKGROUND Prenatal exposures to xenobiotics during the masculinization programming window are suggested to impact male fecundity later in life. Frequently used nitrosatable drugs, such as penicillins and beta2-agonists, contain amines or amides that may form teratogenic compounds in reaction with nitrite. OBJECTIVES We explored whether maternal nitrosatable drug use during gestation was associated with biomarkers of male fecundity in adulthood; moreover, the potential modifiable effect of nitrate and vitamin intake was investigated. METHOD We performed a cohort study in the Fetal Programming of Semen Quality cohort that includes semen characteristics, reproductive hormone concentrations, and measures of testis size on 1058 young adult sons in the Danish National Birth Cohort. Information on maternal use of nitrosatable drugs was obtained from questionnaires and interviews around gestational weeks 11 and 16. A multivariable negative binomial regression model was used to obtain relative differences in biomarkers of male fecundity for those whose mothers used nitrosatable drugs compared to those without such maternal use. In sub-analyses, the exposure was categorized according to nitrosatable drug type: secondary amine, tertiary amine, or amide. We investigated dose dependency by examining the number of weeks with intake and explored potential effect modification by low versus high maternal nitrate and vitamin intake from diet and nitrate concentration in drinking water. We added selection weights and imputed values of missing covariates to limit the risk of selection bias. RESULTS In total, 19.6% of the study population were born of mothers with an intake of nitrosatable drugs at least once during early pregnancy. Relative differences in biomarkers related to male fecundity between exposed and unexposed participants were negligible. Imputation of missing covariates did not fundamentally alter the results. Furthermore, no sensitive subpopulations were detected. CONCLUSIONS The results suggest that maternal use of nitrosatable drugs does not have a harmful influence on the male fecundity of the offspring.
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Affiliation(s)
| | - Nis Brix
- Department of Public Health, Aarhus University, Aarhus, Denmark
- Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
| | - Jörg Schullehner
- Department of Public Health, Aarhus University, Aarhus, Denmark
- Danish Big Data Centre for Environment and Health (BERTHA), Aarhus University, Aarhus, Denmark
| | - Gunnar Toft
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| | - Sandra Søgaard Tøttenborg
- Department of Occupational and Environmental Medicine, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Kobenhavn, Denmark
- Department of Public Health, University of Copenhagen, Kobenhavn, Denmark
| | - Karin Sørig Hougaard
- Department of Public Health, University of Copenhagen, Kobenhavn, Denmark
- National Research Centre for the Working Environment, Kobenhavn, Denmark
| | - Anne Ahrendt Bjerregaard
- Department of Epidemiology Research, Statens Serum Institut, Kobenhavn, Denmark
- Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Kobenhavn, Denmark
| | - Thorhallur Ingi Halldorsson
- Department of Epidemiology Research, Statens Serum Institut, Kobenhavn, Denmark
- Faculty of Food Science and Nutrition, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Sjurdur Frodi Olsen
- Department of Public Health, University of Copenhagen, Kobenhavn, Denmark
- Department of Epidemiology Research, Statens Serum Institut, Kobenhavn, Denmark
| | | | - Leslie Thomas Stayner
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Torben Sigsgaard
- Department of Public Health, Aarhus University, Aarhus, Denmark
- Danish Big Data Centre for Environment and Health (BERTHA), Aarhus University, Aarhus, Denmark
- CIRRAU - Centre for Integrated Register-based Research at Aarhus University, Aarhus, Denmark
| | - Henrik Kolstad
- Department of Occupational Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Jens Peter Ellekilde Bonde
- Department of Occupational and Environmental Medicine, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Kobenhavn, Denmark
- Department of Public Health, University of Copenhagen, Kobenhavn, Denmark
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Pu C, Cavarra BR, Zeng T. Combining High-Resolution Mass Spectrometry and Chemiluminescence Analysis to Characterize the Composition and Fate of Total N-Nitrosamines in Wastewater Treatment Plants. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2024. [PMID: 39254226 PMCID: PMC11428135 DOI: 10.1021/acs.est.4c06555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Abstract
Monitoring the prevalence and persistence of N-nitrosamines and their precursors in wastewater treatment plants (WWTPs) and effluent-receiving aquatic compartments is a priority for utilities practicing wastewater recycling or exploiting wastewater-impacted source waters. In this work, we developed an analytical framework that combines liquid chromatography-high-resolution mass spectrometry (LC-HRMS) with acidic triiodide-chemiluminescence analysis to characterize the composition and fate of total N-nitrosamines (TONO) and their precursors along the treatment trains of eight WWTPs in New York. Through the parallel application of LC-HRMS and chemiluminescence methods, the TONO scores for 41 N-nitrosamines containing structurally diverse substituents on their amine nitrogen were derived based on their solid-phase extraction recoveries and conversion efficiencies to nitric oxide. Correcting the compositional analysis of TONO using the TONO scores of target N-nitrosamines refined the assessment of the reduction or accumulation of TONO and their precursors across treatment steps in WWTPs. Nontargeted analysis prioritized seven additional N-nitrosamines for confirmation by reference standards, including three previously uncharacterized species: N-nitroso-tert-butylphenylamine, N-nitroso-2-pyrrolidinmethanol, and N-nitrosodesloratadine, although they only served as minor components of TONO. Overall, our study establishes an adaptable methodological framework for advancing the quantitative and qualitative analysis of specific and unknown components of TONO across water treatment and reuse scenarios.
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Affiliation(s)
- Changcheng Pu
- Department of Civil and Environmental Engineering, Syracuse University, 151 Link Hall, Syracuse, New York 13244, United States
| | - Benjamin R Cavarra
- Department of Civil and Environmental Engineering, Syracuse University, 151 Link Hall, Syracuse, New York 13244, United States
| | - Teng Zeng
- Department of Civil and Environmental Engineering, Syracuse University, 151 Link Hall, Syracuse, New York 13244, United States
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Paustenbach DJ, Brown SE, Heywood JJ, Donnell MT, Eaton DL. Risk characterization of N-nitrosodimethylamine in pharmaceuticals. Food Chem Toxicol 2024; 186:114498. [PMID: 38341171 DOI: 10.1016/j.fct.2024.114498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 01/23/2024] [Accepted: 01/31/2024] [Indexed: 02/12/2024]
Abstract
Since 2018, N-nitrosodimethylamine (NDMA) has been a reported contaminant in numerous pharmaceutical products. To guide the pharmaceutical industry, FDA identified an acceptable intake (AI) of 96 ng/day NDMA. The approach assumed a linear extrapolation from the Carcinogenic Potency Database (CPDB) harmonic-mean TD50 identified in chronic studies in rats. Although NDMA has been thought to act as a mutagenic carcinogen in experimental animals, it has not been classified as a known human carcinogen by any regulatory agency. Humans are exposed to high daily exogenous and endogenous doses of NDMA. Due to the likelihood of a threshold dose for NDMA-related tumors in animals, we believe that there is ample scientific basis to utilize the threshold-based benchmark dose or point-of-departure (POD) approach when estimating a Permissible Daily Exposure limit (PDE) for NDMA. We estimated that 29,000 ng/kg/day was an appropriate POD for calculating a PDE. Assuming an average bodyweight of 50 kg, we expect that human exposures to NDMA at doses below 5800 ng/day in pharmaceuticals would not result in an increased risk of liver cancer, and that there is little, if any, risk for any other type of cancer, when accounting for the mode-of-action in humans.
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Affiliation(s)
- D J Paustenbach
- Paustenbach and Associates, 970 West Broadway, Suite E, Jackson, WY, USA
| | - S E Brown
- Paustenbach and Associates, 207 Canyon Blvd, Boulder, CO, USA.
| | - J J Heywood
- Paustenbach and Associates, 207 Canyon Blvd, Boulder, CO, USA
| | - M T Donnell
- Valeo Sciences LLC, 333 Corporate Drive, Suite 130, Ladera Ranch, CA, USA
| | - D L Eaton
- Professor Emeritus, Department of Environmental & Occupational Health Sciences, University of Washington, Seattle, WA, USA
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Clemmensen PJ, Brix N, Schullehner J, Ernst A, Harrits Lunddorf LL, Bjerregaard AA, Halldorsson TI, Olsen SF, Hansen B, Stayner LT, Kolstad HA, Sigsgaard T, Ramlau-Hansen CH. Prenatal exposure to nitrosatable drugs and timing of puberty in sons and daughters: A nationwide cohort study. Int J Hyg Environ Health 2023; 254:114271. [PMID: 37820420 DOI: 10.1016/j.ijheh.2023.114271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 09/12/2023] [Accepted: 10/03/2023] [Indexed: 10/13/2023]
Abstract
BACKGROUND N-nitroso compounds (NOCs) can be formed by endogenous reactions between nitrosatable drugs and nitrite. Animal studies have found that several NOCs are teratogenic, and epidemiological studies report associations between prenatal exposure to nitrosatable drugs and adverse birth outcomes. It is unknown whether prenatal exposure to nitrosatable drugs is harmful to the child's reproductive health, including pubertal development. OBJECTIVES We investigated whether prenatal exposure to nitrosatable drugs was associated with timing of puberty and whether nitrate, nitrite and antioxidant intake modified any association. METHODS The population-based Danish National Birth Cohort (DNBC) Puberty Cohort, which includes 15,819 children, was used to investigate the association between prenatal exposure to nitrosatable drugs and timing of puberty. Around gestational week 11 and gestational week 18, mothers provided information about drug use during pregnancy. The children's self-reported information on onset of pubertal milestones was collected every six months from 11 years of age and throughout puberty. To investigate potential effect modification by nitrite, nitrate and antioxidant intake, information on these factors was obtained from a food frequency questionnaire completed by the mothers in gestational week 25, and information on nitrate concentration in maternal drinking water at her residential address was obtained from monitoring data from public waterworks. Data were analysed using a multivariable regression model for interval-censored data estimating difference in months in timing of puberty between exposure groups. RESULTS A total of 2,715 children were prenatally exposed to nitrosatable drugs. We did not find an association between prenatal exposure to nitrosatable drugs and timing of puberty. This finding was supported by null-findings in the following sub-analyses investigating: 1. subtypes of nitrosatable drugs (secondary and tertiary amines and amides), 2. dose-dependency (duration of drug intake), 3. effect modification by maternal intake of nitrate, nitrite, and antioxidants. 4. confounding by indication. CONCLUSIONS Prenatal exposure to nitrosatable drugs was not associated with timing of puberty. Nitrosatable drugs are commonly used drugs in pregnancy, and further research is needed to allow firm conclusions on the potential effect of prenatal exposure to nitrosatable drugs on the child's reproductive health.
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Affiliation(s)
| | - Nis Brix
- Department of Public Health, Aarhus University, Aarhus, Denmark; Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
| | - Jörg Schullehner
- Department of Public Health, Aarhus University, Aarhus, Denmark; Danish Big Data Centre for Environment and Health (BERTHA), Aarhus University, Aarhus, Denmark
| | - Andreas Ernst
- Department of Public Health, Aarhus University, Aarhus, Denmark; Department of Urology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Anne Ahrendt Bjerregaard
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Thorhallur Ingi Halldorsson
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; Faculty of Food Science and Nutrition, School of Health Sciences, University of Iceland, Iceland
| | - Sjurdur Frodi Olsen
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; Section of Epidemiology, Institute of Public Health, University of Copenhagen, Denmark
| | | | - Leslie Thomas Stayner
- Division of Epidemiology and Biostatistics, University of Illinois at Chicago, School of Public Health, Chicago, United States
| | - Henrik Albert Kolstad
- Department of Occupational Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Torben Sigsgaard
- Department of Public Health, Aarhus University, Aarhus, Denmark; Danish Big Data Centre for Environment and Health (BERTHA), Aarhus University, Aarhus, Denmark; Cirrau -Centre for Integrated Register-based Research at Aarhus University, Aarhus, Denmark
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Feng R, Fan Y, Fang Y, Xia Y. Morphological Effects of Au Nanoparticles on Electrochemical Sensing Platforms for Nitrite Detection. Molecules 2023; 28:4934. [PMID: 37446596 DOI: 10.3390/molecules28134934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/17/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Au nanoparticles were synthesized in a soft template of pseudo-polyanions composed of polyvinylpyrrolidone (PVP) and sodium dodecyl sulfate (SDS) by the in situ reduction of chloroauric acid (HAuCl4) with PVP. The particle sizes and morphologies of the Au nanoparticles were regulated with concentrations of PVP or SDS at room temperature. Distinguished from the Au nanoparticles with various shapes, Au nanoflowers (AuNFs) with rich protrusion on the surface were obtained at the low final concentration of SDS and PVP. The typical AuNF synthesized in the PVP (50 g·L-1)-SDS (5 mmol·L-1)-HAuCl4 (0.25 mmol·L-1) solution exhibited a face-centered cubic structure dominated by a {111} crystal plane with an average equivalent particle size of 197 nm and an average protrusion height of 19 nm. Au nanoparticles with four different shapes, nanodendritic, nanoflower, 2D nanoflower, and nanoplate, were synthesized and used to modify the bare glassy carbon electrode (GCE) to obtain Au/GCEs, which were assigned as AuND/GCE, AuNF/GCE, 2D-AuNF/GCE, and AuNP/GCE, respectively. Electrochemical sensing platforms for nitrite detection were constructed by these Au/GCEs, which presented different detection sensitivity for nitrites. The results of cyclic voltammetry (CV) demonstrated that the AuNF/GCE exhibited the best detection sensitivity for nitrites, and the surface area of the AuNF/GCE was 1.838 times of the bare GCE, providing a linear c(NO2-) detection range of 0.01-5.00 µmol·L-1 with a limit of detection of 0.01 µmol·L-1. In addition, the AuNF/GCE exhibited good reproducibility, stability, and high anti-interference, providing potential for application in electrochemical sensing platforms.
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Affiliation(s)
- Ruiqin Feng
- The Key Laboratory of Synthetic and Biological Colloids (Ministry of Education), School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, China
| | - Ye Fan
- The Key Laboratory of Synthetic and Biological Colloids (Ministry of Education), School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, China
| | - Yun Fang
- The Key Laboratory of Synthetic and Biological Colloids (Ministry of Education), School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, China
| | - Yongmei Xia
- The Key Laboratory of Synthetic and Biological Colloids (Ministry of Education), School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, China
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
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10
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Li X, Le Y, Seo JE, Guo X, Li Y, Chen S, Mittelstaedt RA, Moore N, Guerrero S, Sims A, King ST, Atrakchi AH, McGovern TJ, Davis-Bruno KL, Keire DA, Elespuru RK, Heflich RH, Mei N. Revisiting the mutagenicity and genotoxicity of N-nitroso propranolol in bacterial and human in vitro assays. Regul Toxicol Pharmacol 2023; 141:105410. [PMID: 37210026 PMCID: PMC11393638 DOI: 10.1016/j.yrtph.2023.105410] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/05/2023] [Accepted: 05/17/2023] [Indexed: 05/22/2023]
Abstract
Propranolol is a widely used β-blocker that can generate a nitrosated derivative, N-nitroso propranolol (NNP). NNP has been reported to be negative in the bacterial reverse mutation test (the Ames test) but genotoxic in other in vitro assays. In the current study, we systematically examined the in vitro mutagenicity and genotoxicity of NNP using several modifications of the Ames test known to affect the mutagenicity of nitrosamines, as well as a battery of genotoxicity tests using human cells. We found that NNP induced concentration-dependent mutations in the Ames test, both in two tester strains that detect base pair substitutions, TA1535 and TA100, as well as in the TA98 frameshift-detector strain. Although positive results were seen with rat liver S9, the hamster liver S9 fraction was more effective in bio-transforming NNP into a reactive mutagen. NNP also induced micronuclei and gene mutations in human lymphoblastoid TK6 cells in the presence of hamster liver S9. Using a panel of TK6 cell lines that each expresses a different human cytochrome P450 (CYP), CYP2C19 was identified as the most active enzyme in the bioactivation of NNP to a genotoxicant among those tested. NNP also induced concentration-dependent DNA strand breakage in metabolically competent 2-dimensional (2D) and 3D cultures of human HepaRG cells. This study indicates that NNP is genotoxic in a variety of bacterial and mammalian systems. Thus, NNP is a mutagenic and genotoxic nitrosamine and a potential human carcinogen.
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Affiliation(s)
- Xilin Li
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA.
| | - Yuan Le
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Ji-Eun Seo
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Xiaoqing Guo
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Yuxi Li
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Si Chen
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Roberta A Mittelstaedt
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Nyosha Moore
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Sharon Guerrero
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Audrey Sims
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Sruthi T King
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA
| | - Aisar H Atrakchi
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA
| | - Timothy J McGovern
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA
| | - Karen L Davis-Bruno
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA
| | - David A Keire
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA
| | | | - Robert H Heflich
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA
| | - Nan Mei
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA.
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11
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Sirirungreung A, Hansen J, He D, Huang X, Ritz B, Heck JE. Exposure to nitrosatable drugs during pregnancy and childhood cancer: A matched case-control study in Denmark, 1996-2016. Pharmacoepidemiol Drug Saf 2023; 32:496-505. [PMID: 36300575 PMCID: PMC10038857 DOI: 10.1002/pds.5557] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 08/19/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND Nitrosatable drugs can be synthesized to N-nitroso compounds in human stomach. In a pregnant woman, N-nitroso compounds can be translocated to the fetus through the placenta. Maternal exposure of nitrosatable compounds during pregnancy has been associated with childhood brain tumors and leukemia. However, few studies have investigated an association between nitrosatable drug exposure during pregnancy and childhood cancer. We examined if maternal prescriptions of nitrosatable drugs received during pregnancy are associated with childhood cancer. METHODS A matched case-control study was conducted using Danish nationwide registry data from 1995 to 2016. Each childhood cancer case was matched with twenty-five controls. Maternal exposure of nitrosatable drugs during pregnancy was identified from the Danish National Prescription Register. A multivariable conditional logistic regression model was used to estimate adjusted odds ratios (adj.OR) with 95% confidence intervals (CI) for each childhood cancer type. RESULTS Maternal prescriptions of nitrosatable drugs positively associate with central nervous system tumors (adj.OR = 1.25; 95% CI = 1.04-1.51) and neuroblastoma (adj.OR = 1.96; 95% CI = 1.34-2.85) in offspring. We also observed a positive association between perinatal exposure of nitrosatable drugs and acute lymphoblastic leukemia (adj.OR = 1.31; 95% CI = 1.07-1.59), however, it appeared to be due to confounding by indication, i.e., maternal infections. CONCLUSION Nitrosatable drug use during pregnancy potentially increased risk of central nervous system tumors and neuroblastoma. While a positive association between maternal prescriptions of nitrosatable drugs and acute lymphoblastic leukemia should be interpreted cautiously because of confounding by indication.
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Affiliation(s)
- Anupong Sirirungreung
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California, USA
| | - Johnni Hansen
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Di He
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California, USA
| | - Xiwen Huang
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California, USA
| | - Beate Ritz
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California, USA
| | - Julia E Heck
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, California, USA
- College of Health and Public Service, University of North Texas, Denton, Texas, USA
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12
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Golob N, Peterlin S, Grahek R, Roškar R. NDMA formation Due to Active Ingredient Degradation and Nitrite Traces in Drug Product. J Pharm Sci 2023; 112:1277-1286. [PMID: 36925105 DOI: 10.1016/j.xphs.2023.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/28/2023] [Accepted: 03/09/2023] [Indexed: 03/16/2023]
Abstract
N-nitrosamines are genotoxic compounds which can be found as impurities in drug substances and drug products used in the pharmaceutical industry. To date, several possible nitrosamine sources in drug products have been reported and this study aims to illuminate another one. A case of afatinib drug product was investigated, in which up to 50 ppb N-nitrosodimethylamine (NDMA) traces were detected. Afatinib was found to degrade to the secondary amine dimethylamine (DMA), forming NDMA with traces of nitrite in crospovidone. Two series of film-coated tablets were prepared with crospovidone from two different manufacturers, containing different levels of nitrites. Tablets were subjected to an accelerated stability study (40 °C/75% relative humidity) or stored at room temperature and levels of NDMA, DMA and nitrite in tablets were monitored. NDMA and nitrite were found on ppb levels, whereas DMA was detected on ppm levels. NDMA formation in the drug product was found to be time, temperature and nitrite dependent and it was emphasized that DMA and nitrite should be reduced. The accelerated stability study proved to be a useful tool for predicting nitrosamine formation in the drug product.
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Affiliation(s)
- Nejc Golob
- Lek Pharmaceuticals d.d., Sandoz Development Center Slovenia, Ljubljana, Slovenia; University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia
| | - Simona Peterlin
- Lek Pharmaceuticals d.d., Sandoz Development Center Slovenia, Ljubljana, Slovenia
| | - Rok Grahek
- Lek Pharmaceuticals d.d., Sandoz Development Center Slovenia, Ljubljana, Slovenia
| | - Robert Roškar
- University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
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13
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Wichitnithad W, Nantaphol S, Noppakhunsomboon K, Thitikornpong W, Rojsitthisak P. Current status and prospects of development of analytical methods for determining nitrosamine and N-nitroso impurities in pharmaceuticals. Talanta 2023; 254:124102. [PMID: 36470020 DOI: 10.1016/j.talanta.2022.124102] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 11/07/2022] [Accepted: 11/14/2022] [Indexed: 11/18/2022]
Abstract
Nitrosamine impurities in pharmaceuticals have recently been concerned for several national regulatory agencies to avoid carcinogenic and mutagenic effects in patients. The demand for highly sensitive and specific analytical methods with LOQs in the ppb and sub-ppb ranges is among the most significant challenges facing analytical scientists. In addition, artifactual nitrosamine formation during sample preparation and injection leading to overestimation of nitrosamines has received considerable attention. Numerous analytical methodologies have been reported for quantifying nitrosamine impurities in active pharmaceutical ingredients and medicinal products at the interim limit criteria as preventive measures. In this review, we meticulously discuss those reported gas and liquid chromatographic methods for nitrosamine determination in pharmaceuticals in aspects of chromatographic conditions and sensitivity of detection. We also introduce the potential of novel fluorescence-based methods recently developed to rapidly screen nitrosamine impurities. In addition, the review assesses the nitrosation assay procedure (NAP test), which is expected to be a future preventive measure for screening potential nitrosation and identifying suspected contamination with N-nitroso or other potential mutagenic impurities during the drug development process.
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Affiliation(s)
- Wisut Wichitnithad
- Department of Analytical Development, Pharma Nueva Co., Ltd., Bangkok, 10900, Thailand; Department of Clinical Development, Pharma Nueva Co., Ltd., Bangkok, 10900, Thailand
| | - Siriwan Nantaphol
- Department of Clinical Development, Pharma Nueva Co., Ltd., Bangkok, 10900, Thailand
| | | | - Worathat Thitikornpong
- Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand; Center of Excellence in Natural Products for Ageing and Chronic Diseases, Chulalongkorn University, Bangkok 10330, Thailand
| | - Pornchai Rojsitthisak
- Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand; Center of Excellence in Natural Products for Ageing and Chronic Diseases, Chulalongkorn University, Bangkok 10330, Thailand.
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14
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Horne S, Vera MD, Nagavelli LR, Sayeed VA, Heckman L, Johnson D, Berger D, Yip YY, Krahn CL, Sizukusa LO, Rocha NFM, Bream RN, Ludwig J, Keire DA, Condran G. Regulatory Experiences with Root Causes and Risk Factors for Nitrosamine Impurities in Pharmaceuticals. J Pharm Sci 2023; 112:1166-1182. [PMID: 36599405 DOI: 10.1016/j.xphs.2022.12.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/19/2022] [Accepted: 12/23/2022] [Indexed: 01/02/2023]
Abstract
N-Nitrosamines (also referred to as nitrosamines) are a class of substances, many of which are highly potent mutagenic agents which have been classified as probable human carcinogens. Nitrosamine impurities have been a concern within the pharmaceutical industry and by regulatory authorities worldwide since June 2018, when regulators were informed of the presence of N-nitrosodimethylamine (NDMA) in the angiotensin-II receptor blocker (ARB) medicine, valsartan. Since that time, regulatory authorities have collaborated to share information and knowledge on issues related to nitrosamines with a goal of promoting convergence on technical issues and reducing and mitigating patient exposure to harmful nitrosamine impurities in human drug products. This paper shares current scientific information from a quality perspective on risk factors and potential root causes for nitrosamine impurities, as well as recommendations for risk mitigation and control strategies.
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Affiliation(s)
| | - Matthew D Vera
- US Food and Drug Administration (US FDA), Silver Spring, MD, 20993, USA
| | - Laxma R Nagavelli
- US Food and Drug Administration (US FDA), Silver Spring, MD, 20993, USA
| | - Vilayat A Sayeed
- US Food and Drug Administration (US FDA), Silver Spring, MD, 20993, USA
| | - Laurel Heckman
- US Food and Drug Administration (US FDA), Silver Spring, MD, 20993, USA
| | - Deborah Johnson
- US Food and Drug Administration (US FDA), Silver Spring, MD, 20993, USA
| | - Dan Berger
- US Food and Drug Administration (US FDA), Silver Spring, MD, 20993, USA
| | | | | | | | | | - Robert N Bream
- European Medicines Agency (EMA, EU), Amsterdam, the Netherlands
| | - Joachim Ludwig
- Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), Bonn, Germany
| | - David A Keire
- US Food and Drug Administration (US FDA), St Louis, MO, 63110, USA
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15
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Ebdrup NH, Schullehner J, Knudsen UB, Liew Z, Thomsen AML, Lyngsø J, Bay B, Arendt LH, Clemmensen PJ, Sigsgaard T, Hansen B, Ramlau-Hansen CH. Drinking water nitrate and risk of pregnancy loss: a nationwide cohort study. Environ Health 2022; 21:87. [PMID: 36114546 PMCID: PMC9479399 DOI: 10.1186/s12940-022-00897-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 09/01/2022] [Indexed: 05/12/2023]
Abstract
BACKGROUND Nitrate contamination is seen in drinking water worldwide. Nitrate may pass the placental barrier. Despite suggestive evidence of fetal harm, the potential association between nitrate exposure from drinking water and pregnancy loss remains to be studied. We aimed to investigate if nitrate in drinking water was associated with the risk of pregnancy loss. METHODS We conducted a nationwide cohort study of 100,410 pregnancies (enrolled around gestational week 11) in the Danish National Birth Cohort (DNBC) during 1996-2002. Spontaneous pregnancy losses before gestational week 22 were ascertained from the Danish National Patient Registry and DNBC pregnancy interviews. Using the national drinking water quality-monitoring database Jupiter, we estimated the individual and time-specific nitrate exposure by linking geocoded maternal residential addresses with water supply areas. The nitrate exposure was analyzed in spline models using a log-transformed continuous level or classified into five categories. We used Cox proportional hazards models to estimate associations between nitrate and pregnancy loss and used gestational age (days) as the time scale, adjusting for demographic, health, and lifestyle variables. RESULTS No consistent associations were found when investigating the exposure as a categorical variable and null findings were also found in trimester specific analyses. In the spline model using the continuous exposure variable, a modestly increased hazard of pregnancy loss was observed for the first trimester at nitrate exposures between 1 and 10 mg/L, with the highest. adjusted hazard ratio at 5 mg/L of nitrate of 1.16 (95% CI: 1.01, 1.34). This trend was attenuated in the higher exposure ranges. CONCLUSION No association was seen between drinking water nitrate and the risk of pregnancy loss when investigating the exposure as a categorical variable. When we modelled the exposure as a continuous variable, a dose-dependent association was found between drinking water nitrate exposure in the first trimester and the risk of pregnancy loss. Very early pregnancy losses were not considered in this study, and whether survival bias influenced the results should be further explored.
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Affiliation(s)
- Ninna Hinchely Ebdrup
- Department of Obstetrics and Gynecology, Horsens Fertility Clinic, Horsens, Denmark.
- Department of Public Health, Aarhus University, Aarhus, Denmark.
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| | - Jörg Schullehner
- Department of Public Health, Aarhus University, Aarhus, Denmark
- Geological Survey of Denmark and Greenland, Aarhus, Denmark
| | - Ulla Breth Knudsen
- Department of Obstetrics and Gynecology, Horsens Fertility Clinic, Horsens, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Zeyan Liew
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
- Yale Center for Perinatal, Pediatric, and Environmental Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | - Anne Marie Ladehoff Thomsen
- Department of Public Health, Aarhus University, Aarhus, Denmark
- DEFACTUM - Public Health & Health Services Research, Central Denmark Region, Aarhus, Denmark
| | - Julie Lyngsø
- Department of Public Health, Aarhus University, Aarhus, Denmark
- Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark
| | - Bjørn Bay
- Department of Obstetrics and Gynecology, Horsens Fertility Clinic, Horsens, Denmark
- Maigaard Fertility Clinic, Aarhus, Denmark
| | - Linn Håkonsen Arendt
- Department of Public Health, Aarhus University, Aarhus, Denmark
- Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Torben Sigsgaard
- Department of Public Health, Aarhus University, Aarhus, Denmark
- Centre for Integrated Register-Based Research Aarhus University, Aarhus, Denmark
- Danish Big Data Centre for Environment and Health (BERTHA), Aarhus University, Aarhus, Denmark
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16
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Jireš J, Douša M, Gibala P, Kubelka T. N-Nitrosation in the absence of nitrosating agents in pharmaceuticals? J Pharm Biomed Anal 2022; 218:114872. [PMID: 35696937 DOI: 10.1016/j.jpba.2022.114872] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/23/2022] [Accepted: 05/31/2022] [Indexed: 11/26/2022]
Abstract
The possibility of N-Nitrosation in the absence of nitrosating agents was studied on model solutions and film coated tablets containing metformin. N-nitrosodimethylamine (NDMA) and N-nitrosation precursors (dimethylamine and nitrites) were determined using previously published fully validated analytical methods. Alternative routes to N-nitrosation were found. Dimethylamine can undergo an oxidation to nitrite in the presence of strong oxidants (e.g., H2O2), as was observed during wastewater treatment in several published works. The resulting nitrite can consecutively act as a nitrosating agent. We proved that the described reaction indeed leads to N-nitrosation (NDMA formation in case of dimethylamine precursor) in model solutions made of dimethylamine and H2O2. An experiment was designed in order to prove those reactions take place in dosage forms. Film coated tablets present a highly heterogenous system with several solid phases and low water activity, which is in stark contrast to the liquid wastewater, where this reaction was originally studied. Despite that, the described reaction took place even in the tablets, but only to a small degree. The amount formed via this alternative route corresponds to less than 10 % of the total formed NDMA. The pH optimum of this alternative route lies in the alkaline range which was confirmed by the determined NDMA concentration in model solutions. The solid phase system (i.e., tablets) was found to behave differently. The addition of Na2CO3 into the tablets during manufacture resulted in tablets without NDMA (cNDMA < LOQ) even in batches spiked with both dimethylamine and H2O2. Thus, adjusting the pH of the solid dosage forms remains a sufficient measure of controlling N-nitrosamines in the product, even in product with limit amounts of oxidating agent (H2O2) and N-nitrosation precursor (dimethylamine).
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Affiliation(s)
- Jakub Jireš
- Department of Analytical chemistry, Faculty of Chemical Engineering, UCT Prague, Technická 5, Prague 6 166 28, Czech Republic
| | - Michal Douša
- Zentiva, k.s. Praha, U Kabelovny 130, Prague 10 102 37, Czech Republic.
| | - Petr Gibala
- Zentiva, k.s. Praha, U Kabelovny 130, Prague 10 102 37, Czech Republic
| | - Tomáš Kubelka
- Zentiva, k.s. Praha, U Kabelovny 130, Prague 10 102 37, Czech Republic
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17
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Nitrites as precursors of N-nitrosation in pharmaceutical samples – A trace level analysis. J Pharm Biomed Anal 2022; 213:114677. [DOI: 10.1016/j.jpba.2022.114677] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 02/01/2022] [Accepted: 02/15/2022] [Indexed: 11/21/2022]
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18
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Schmidtsdorff S, Neumann J, Schmidt AH, Parr MK. Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development. Arch Pharm (Weinheim) 2022; 355:e2100435. [PMID: 35088435 DOI: 10.1002/ardp.202100435] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/26/2021] [Accepted: 12/30/2021] [Indexed: 11/09/2022]
Abstract
Since June 2018, thousands of drug products from around the world had to be recalled due to the unexpected presence of nitrosamines (NAs). Starting with the pharmaceutical group of sartans, antidiabetic drugs, antihistamines, and antibiotics also became the subject of investigation. The occurrence of NAs has shown that pharmaceutical companies and regulatory agencies did not focus on these substances in the past during drug development. In this study, we incorporated a nitrosation assay procedure into high-resolution supercritical fluid chromatography (SFC)-mass spectrometry screening to test the potential of direct nitrosation of active pharmaceutical ingredients (APIs). The forced degradation study was performed with a four-fold molar excess of sodium nitrite, relative to the drug substance, at pH 3-4 for 4 h at 37°C. Chromatographic separation was performed on a porous graphitic carbon column by SFC. The mass analysis then focused on direct N-nitrosation or N-nitroso compounds (NOCs) formed after dealkylation. Substances (n = 67) from various pharmaceutical classes were evaluated and 49.3% of them formed NOCs, of which 21.2% have not yet been reported in the literature. In addition, for two APIs, which are known to form an unidentified NOC, the structure could be identified. A few substances also showed multiple NOCs and even N,N'-dinitroso-species. As NAs are carcinogens, they have to be eliminated or at least limited to prevent cancer in patients, who rely on these drugs. This study contributes a procedure that can be implemented in preapproval drug development and postapproval risk assessment to prevent unexpected findings in the future.
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Affiliation(s)
- Sebastian Schmidtsdorff
- Chromicent GmbH, Berlin, Germany.,Department of Biology, Chemistry, and Pharmacy, Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany
| | - Jonas Neumann
- Chromicent GmbH, Berlin, Germany.,Department of Biology, Chemistry, and Pharmacy, Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany
| | | | - Maria K Parr
- Department of Biology, Chemistry, and Pharmacy, Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany
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19
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Thomsen AML, Ramlau-Hansen CH, Schullehner J, Ebdrup NH, Liew Z, Coffman V, Stayner L, Hansen B, Olsen J. Prenatal nitrosatable prescription drug intake, drinking water nitrate, and the risk of stillbirth: a register- and population-based cohort of Danish pregnancies, 1997-2017. Environ Health 2021; 20:118. [PMID: 34781958 PMCID: PMC8594235 DOI: 10.1186/s12940-021-00805-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 11/08/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Nitrosatable drugs commonly prescribed during pregnancy can react with nitrite to form N-nitroso compounds which have been associated with an increased risk of stillbirth. Whether maternal residential drinking water nitrate modifies this association is unknown. We investigated, if household drinking water nitrate was associated with stillbirth, and if it modified the association between nitrosatable prescription drug intake and the risk of stillbirth. METHODS We conducted an individual-level register- and population-based cohort study using 652,810 women with the first recorded singleton pregnancy in the Danish Medical Birth Registry between 1997 and 2017. Nitrosatable drug exposure was recorded by use of the Danish National Patient Registry defined as women with a first redeemed prescription of a nitrosatable drug the first 22 weeks of pregnancy. The reference group was women with no redeemed prescription of a nitrosatable drug in this period. The average individual drinking water nitrate concentration level (mg/L) was calculated in the same period. We categorized nitrosatable drugs as secondary amines, tertiary amines, and amides. Cox hazard regression was used to estimate crude and adjusted hazard ratios with 95% confidence intervals for stillbirth stratified into five categories of nitrate concentrations: ≤1 mg/L, > 1- ≤ 2 mg/L, > 2- ≤ 5 mg/L, > 5- ≤ 25 mg/L, and > 25 mg/L. RESULTS Drinking water nitrate exposure in the population was not associated with the risk of stillbirth. Among 100,244 women who had a nitrosatable prescription drug redeemed ≤22 weeks of pregnancy of pregnancy, 418 (0.42%) had a stillbirth compared to 1993 stillbirths (0.36%) among 552,566 referent women. Women with any nitrosatable prescription drug intake and > 1- ≤ 2 mg/L nitrate concentration had an increased risk of stillbirth [adjusted hazard ratio 1.55 (95% confidence interval, 1.15-2.09)] compared with referent women. In the stratified analyses, the highest risk of stillbirth was found among women with secondary amine intake and > 25 mg/L nitrate concentrations [adjusted hazard ratio 3.11 (95% CI, 1.08-8.94)]. CONCLUSIONS The association between nitrosatable prescription drug intake and the risk of stillbirth may depend on the level of nitrate in household drinking water. Evaluations of the effect of nitrosatable drug intake on perinatal outcomes might consider nitrate exposure from drinking water.
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Affiliation(s)
- Anne Marie Ladehoff Thomsen
- DEFACTUM, Public Health & Health Services Research, Central Denmark Region, Olof Palmes Allé 15, 8200, Aarhus N, Denmark.
- Department of Public Health, Aarhus University, Aarhus, Denmark.
| | | | - Jörg Schullehner
- Department of Public Health, Aarhus University, Aarhus, Denmark
- Department of Groundwater and Quaternary Geology Mapping, Geological Survey of Denmark and Greenland, Aarhus, Denmark
- Center for Integrated Research-based Research, Aarhus University, Aarhus, Denmark
| | | | - Zeyan Liew
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
- Yale Center for Perinatal, Pediatric, and Environmental Epidemiology, Yale School of Public Health, New Haven, USA
| | - Vanessa Coffman
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA
| | - Leslie Stayner
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA
| | - Birgitte Hansen
- Department of Groundwater and Quaternary Geology Mapping, Geological Survey of Denmark and Greenland, Aarhus, Denmark
| | - Jørn Olsen
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
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Gomes LM, Moysés DA, Nascimento HFS, Mota TC, Bonfim LT, Cardoso PCS, Burbano RMR, Bahia MO. Genotoxic and cytotoxic effects of the drug dipyrone sodium in African green monkey kidney (Vero) cell line exposed in vitro. Naunyn Schmiedebergs Arch Pharmacol 2021; 394:1529-1535. [DOI: 10.1007/s00210-021-02078-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 03/08/2021] [Indexed: 12/13/2022]
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21
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Seid MG, Chung J, Choe J, Cho K, Hong SW. Role of ranitidine in N-nitrosodimethylamine formation during chloramination of competing micropollutants. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 756:144156. [PMID: 33302063 DOI: 10.1016/j.scitotenv.2020.144156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/24/2020] [Accepted: 11/26/2020] [Indexed: 06/12/2023]
Abstract
Ranitidine (RNT) is a widely known precursor of N-nitrosodimethylamine (NDMA) as evinced by the self-catalytic formation of NDMA during chloramination. In the present study, the NDMA formation potentials (NDMA-FP) of 26 micropollutants were assessed, particularly when mixed with RNT. 11 compounds were identified as individual precursors, including trimebutine and cimetidine, which exhibited substantial NDMA-FP, with up to 10% molar yield. In addition, nitrosamines, other than NDMA, namely N-nitrosodiethylamine and N-nitrosomethylamine, were observed from diethylamine-containing precursors, such as metoclopramide. In a 1:1 mixture of RNT and a competitor, the change in NDMA-FP was mostly comparable (within 20% deviation), while antagonistic interactions were observed for competitors, such as diethylhydroxylamine. The scattered overall NDMA-FP should be considered as a product of competition among the precursors for core substrates and intermediates for NDMA formation. The co-existence of either trimebutine or metoclopramide with RNT led to an exceptionally synergetic NDMA generation. Degradation kinetics and chlorination/nitrosation experiments combined with mass spectroscopy analyses indicated that RNT would accelerate both the initial chlorination and nitrosation of trimebutine and metoclopramide, leading to N-nitroso complexes, which have well-understood NDMA formation pathways, i.e., amination with subsequent aminyl radical generation. This work demonstrates a wide array of precursors with NDMA-FP, suggesting that nitrosamine formation is potentially underestimated in field environments.
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Affiliation(s)
- Mingizem Gashaw Seid
- Division of Energy and Environment Technology, KIST-School, University of Science and Technology, Seoul 02792, Republic of Korea; Water Cycle Research Center, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea
| | - Jaeshik Chung
- Water Cycle Research Center, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea
| | - Jaewan Choe
- Department of Civil Engineering, Gwangju University, Gwangju 61743, Republic of Korea
| | - Kangwoo Cho
- Division of Environmental Science and Engineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea; Institute for Convergence Research and Education in Advanced Technology (I-CREATE), Yonsei University, Incheon 406-840, Republic of Korea.
| | - Seok Won Hong
- Division of Energy and Environment Technology, KIST-School, University of Science and Technology, Seoul 02792, Republic of Korea; Water Cycle Research Center, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea.
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22
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Shen Y, Ma C, Zhang S, Li P, Zhu W, Zhang X, Gao J, Song H, Chen D, Pang D, Li A. Nanosilver and protonated carbon nitride co-coated carbon cloth fibers based non-enzymatic electrochemical sensor for determination of carcinogenic nitrite. THE SCIENCE OF THE TOTAL ENVIRONMENT 2020; 742:140622. [PMID: 32721742 DOI: 10.1016/j.scitotenv.2020.140622] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/27/2020] [Accepted: 06/28/2020] [Indexed: 06/11/2023]
Abstract
A novel electrochemical nitrite (NaNO2) sensor was fabricated by combining nanosilver with protonated carbon nitride (H-C3N4) supported on carbon cloth (CC). H-C3N4 was distributed uniformly on the CC surface, providing more active sites for the electrocatalytic active center (nanosilver). CC as a substrate improved the H-C3N4 conductivity and provided the sensor with a flexible feature. The strong synergistic effect between CC, H-C3N4, and nanosilver can exert a significant electrocatalytic performance on the flexible sensor. The Ag/H-C3N4/CC flexible sensor electrode did not consume much more time to polish the surface of traditional electrodes, and possessed a high sensitivity of 0.85537 μA/mg, a wide linear response range that spanned 5 to 1000 μM, a low detection limit of 0.216 μM (S/N = 3), and high selectivity for nitrite in the presence of common organic and inorganic interfering species (such as CaCl2, NaCl, MgCl2, NaNO3, glucose, urea, and p-nitrophenol). The Ag/H-C3N4/CC flexible sensor can be used for sample detection of nitrite as it has a strong anti-interference ability, good reproducibility, repeatability, and long-term stability. The Ag/H-C3N4/CC sensor is a promising alternative electrode to traditional ones such as ITO, gold or glassy carbon electrodes.
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Affiliation(s)
- Yuliang Shen
- School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, PR China
| | - Chuang Ma
- School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, PR China
| | - Shupeng Zhang
- School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, PR China; State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, PR China; Nanjing University & Yancheng Academy of Environmental Protection Technology and Engineering, Yancheng 210009, PR China.
| | - Pengcheng Li
- Hubei Key Laboratory of Plasma Chemistry and Advanced Materials, School of Materials Science and Engineering, Wuhan Institute of Technology, Wuhan 430205, PR China.
| | - Weiqing Zhu
- School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, PR China
| | - Xumei Zhang
- School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, PR China
| | - Juanjuan Gao
- School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, PR China
| | - Haiou Song
- School of Environment, Nanjing Normal University, Nanjing 210097, PR China.
| | - Duozhe Chen
- School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, PR China
| | - Di Pang
- School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, PR China
| | - Aimin Li
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, PR China; Nanjing University & Yancheng Academy of Environmental Protection Technology and Engineering, Yancheng 210009, PR China.
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Brienza M, Manasfi R, Sauvêtre A, Chiron S. Nitric oxide reactivity accounts for N-nitroso-ciprofloxacin formation under nitrate-reducing conditions. WATER RESEARCH 2020; 185:116293. [PMID: 32818734 DOI: 10.1016/j.watres.2020.116293] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 08/07/2020] [Accepted: 08/11/2020] [Indexed: 06/11/2023]
Abstract
The formation of N-nitroso-ciprofloxacin (CIP) was investigated both in wastewater treatment plants including nitrification/denitrification stages and in sludge slurry experiments under denitrifying conditions. The analysis of biological wastewater treatment plant effluents by Kendrick mass defect analysis and liquid chromatography - high resolution - mass spectrometry (LCHRMS) revealed the occurrence of N-nitroso-CIP and N-nitroso-hydrochlorothiazide at concentration levels of 34 ± 3 ng/L and 71 ± 6 ng/L, respectively. In laboratory experiments and dark conditions, produced N-nitroso-CIP concentrations reached a plateau during the course of biodegradation experiments. A mass balance was achieved after identification and quantification of several transformation products by LCHRMS. N-nitroso-CIP accounted for 14.3% of the initial CIP concentration (20 µg/L) and accumulated against time. The use of 4,5-diaminofluorescein diacetate and superoxide dismutase as scavengers for in situ production of nitric oxide and superoxide radical anion respectively, revealed that the mechanisms of formation of N-nitroso-CIP likely involved a nitrosation pathway through the formation of peroxynitrite and another one through codenitrification processes, even though the former one appeared to be prevalent. This work extended the possible sources of N-nitrosamines by including a formation pathway relying on nitric oxide reactivity with secondary amines under activated sludge treatment.
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Affiliation(s)
- Monica Brienza
- UMR HydroSciences Montpellier, Montpellier University, IRD, 15 Ave Charles Flahault 34093 Montpellier cedex 5, France
| | - Rayana Manasfi
- UMR HydroSciences Montpellier, Montpellier University, IRD, 15 Ave Charles Flahault 34093 Montpellier cedex 5, France
| | - Andrés Sauvêtre
- UMR HydroSciences Montpellier, Montpellier University, IRD, 15 Ave Charles Flahault 34093 Montpellier cedex 5, France
| | - Serge Chiron
- UMR HydroSciences Montpellier, Montpellier University, IRD, 15 Ave Charles Flahault 34093 Montpellier cedex 5, France.
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Giri A, Das A, Sarkar AK, Giri AK. Mutagenic, Genotoxic and Immunomodulatory effects of Hydroxychloroquine and Chloroquine: a review to evaluate its potential to use as a prophylactic drug against COVID-19. Genes Environ 2020; 42:25. [PMID: 32884603 PMCID: PMC7462746 DOI: 10.1186/s41021-020-00164-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 08/20/2020] [Indexed: 12/19/2022] Open
Abstract
Hydroxychloroquine (HCQ) and Chloroquine (CQ) are two anti-malarial drugs that are now being extensively used by front-line healthcare workers and other common people as a prophylactic drug against the Corona Virus Disease − 19 (COVID-19) in India and as well as in many parts of the world. While only a few in vitro studies have pointed to some efficacy of these drugs as a prophylactic against COVID-19, to date, there are no clinical studies that have established any clinical efficacy of these drugs as a prophylactic. These drugs are commonly used for the treatment of Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) because of its immunomodulatory effects. Previously, we have evaluated the genetic toxicology of different drugs and chemicals including antimalarial drug CQ both in vitro and in vivo. Thus, we recognize the need to critically review the mutagenic, genotoxic, and immunomodulatory effects of these drugs, to find out whether it is safe to use as a prophylactic drug against COVID-19. Existing literature suggests that CQ can induce mutagenic and genotoxic effects in multiple test systems and both the drugs have immunomodulatory effects. There was no data available to evaluate the mutagenicity and genotoxicity for HCQ. However, during metabolism about 60% of both the drugs remain unchanged and about 40% of the drugs are metabolized into two metabolites, desethylchloroquine and bisdesethylchloroquine by the action of the cytochrome P450 (CYP) enzymes in the liver. Both HCQ and CQ are immunomodulatory drugs and have the potential to suppress normal immune system activation. In this review, we have elucidated the mechanism of immunomodulation by both HCQ and CQ and highlighted the mutagenic and genotoxic effects from the available literature. This article is written with the sole objective that the reader will be able to recognize the adverse effects of these drugs when consumed by healthy individuals as a prophylactic. Current literature indicates that healthy individuals should refrain from the use of these drugs until further investigation.
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Affiliation(s)
- Allan Giri
- Department of Biomedical Science, Kansas City University of Medicine and Biosciences, Kansas City, MO 64106 USA
| | - Ankita Das
- Department of Environmental Sciences, University of Calcutta, Kolkata, 700019 India
| | - Ajoy K Sarkar
- Intensive Care Unit, Peerless Hospital, B.K. Roy Research Centre, Kolkata, 700094 India
| | - Ashok K Giri
- Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700032 India
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A systematic review on the genotoxic effect of serotonin and norepinephrine reuptake inhibitors (SNRIs) antidepressants. Psychopharmacology (Berl) 2020; 237:1909-1915. [PMID: 32529266 DOI: 10.1007/s00213-020-05550-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 05/11/2020] [Indexed: 12/12/2022]
Abstract
RATIONALE Depression is a major mental disorder affecting millions of people worldwide. Serotonin and norepinephrine reuptake inhibitors (SNRIs) are one of the antidepressant drugs prescribed for depression treatment. OBJECTIVE AND METHOD There are many contradiction studies about the adverse effect and genotoxicity of SNRIs. So here, based on the guidelines proposed at the PRISMA statement, we performed a quantitative systematic review by searching international electronic databases (PubMed, Scopus, Embase, and Web of Science) for published documents on SSNRIs and their genotoxicity effects. RESULTS The database searches retrieved 336 records, 18 of which met the inclusion criteria. Evaluation of the selected articles showed that a total of 9 articles were appropriate for final review. Most of these studies (78%) reported positive results for the genotoxicity of SNRIs CONCLUSION: Finally, we can conclude that these drugs have the potential to damage DNA.
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Omaye AT, Omaye ST. Caveats for the Good and Bad of Dietary Red Meat. Antioxidants (Basel) 2019; 8:E544. [PMID: 31726758 PMCID: PMC6912709 DOI: 10.3390/antiox8110544] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 11/04/2019] [Accepted: 11/06/2019] [Indexed: 12/21/2022] Open
Abstract
Red meat and its constituents of heme iron or free iron have been the target of scrutiny related to their purported association to many chronic diseases. However, in contrast, red meat provides a rich source of nutrition. In 2007, Al Tappel hypothesized that the mechanistic explanation for the adverse impact of iron and heme iron could be the strong influence these substances have in initiating and promoting oxidative stress. Also, there is an emphasis on the importance of dietary antioxidants in the modulation of these adverse effects. The goal of this argumentative review is to provide an update of the importance of dietary red meat for health, and the hypothesis that oxidative stress initiated by dietary iron and heme iron may be related to chronic diseases, with a particular emphasis on recent research that impacts the paradigm. We also examine potential dietary changes that could substantially modify the potential adverse outcomes of chronic diseases initiated by heme iron mechanisms, e.g., consumption of antioxidant-rich fruits and vegetables.
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Affiliation(s)
| | - Stanley T. Omaye
- Department of Nutrition, University of Nevada, Reno, NE 89557, USA
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Complementary HPLC, in silico toxicity, and molecular docking studies for investigation of the potential influences of gastric acidity and nitrite content on paracetamol safety. Microchem J 2019. [DOI: 10.1016/j.microc.2019.104107] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Brienza M, Manasfi R, Chiron S. Relevance of N-nitrosation reactions for secondary amines in nitrate-rich wastewater under UV-C treatment. WATER RESEARCH 2019; 162:22-29. [PMID: 31254883 DOI: 10.1016/j.watres.2019.06.055] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 06/18/2019] [Accepted: 06/20/2019] [Indexed: 06/09/2023]
Abstract
This study investigated the transformation of secondary amine pharmaceuticals in UV-C/NO3- and in nitrate-rich wastewater at 254 nm by taking diclofenac, diphenylamine, mefenamic acid and furosemide as probe compounds. The degradation of targeted compounds were positively related to nitrate concentration and mainly caused by the formation of peroxynitrite and related reactive nitrogen species (e.g., nitrogen oxide and nitrogen dioxide radicals). Major transformation products were identified to provide fundamental understanding of the selective oxidation of secondary amine with reactive nitrogen species. UV photolysis, hydroxyl radical oxidation, nitration and nitrosation processes were found to be the most significant transformation pathways. In case of diphenylamine, for which most of the identified intermediates were available as standard, the relative significance of each transformation route could be established, highlighting for the first time the important role of N-nitrosation processes in UV/NO3- treatment followed by the decomposition of the resulting N-nitroso compounds by an alpha hydroxylation mechanism. This specific transformation pathway was of concern because it constitutes the molecular basis of N-nitrosamine carcinogenicity and may contribute to the increase in effluent genotoxicity under UV-C treatment in addition to the formation of nitrophenols. Hydrogenocarbonate ions at concentration values higher than 300 mg/L appeared to be a protective specie against nitrosation processes due to the formation of carbamate adducts but H2O2 in UV-C/H2O2 could be responsible for an exacerbation of the N-nitrosation pathway due to an addition source of hydroxyl radical in the system. The occurrence of major transformation products of diclofenac was confirmed in nitrate-rich wastewater under UV-C treatment at pilot-scale operation.
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Affiliation(s)
- Monica Brienza
- UMR HydroSciences Montpellier, Montpellier University, IRD, 15 Ave Charles Flahault 34093 Montpellier Cedex 5, France
| | - Rayana Manasfi
- UMR HydroSciences Montpellier, Montpellier University, IRD, 15 Ave Charles Flahault 34093 Montpellier Cedex 5, France
| | - Serge Chiron
- UMR HydroSciences Montpellier, Montpellier University, IRD, 15 Ave Charles Flahault 34093 Montpellier Cedex 5, France.
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El-Shaheny R, Radwan M, Yamada K, El-Maghrabey M. Estimation of nizatidine gastric nitrosatability and product toxicity via an integrated approach combining HILIC, in silico toxicology, and molecular docking. J Food Drug Anal 2019; 27:915-925. [PMID: 31590763 PMCID: PMC9306978 DOI: 10.1016/j.jfda.2019.08.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 07/29/2019] [Accepted: 08/06/2019] [Indexed: 01/05/2023] Open
Abstract
The liability of the H2-receptor antagonist nizatidine (NZ) to nitrosation in simulated gastric juice (SGJ) and under WHO-suggested conditions was investigated for the first time. For monitoring the nitrosatability of NZ, a hydrophilic interaction liquid chromatography (HILIC) method was optimized and validated according to FDA guidance. A Cosmosil HILIC® column and a mobile phase composed of acetonitrile: 0.04 M acetate buffer pH 6.0 (92:8, v/v) were used for the separation of NZ and its N-nitroso derivative (NZ-NO) within 6 min with LODs of 0.02 and 0.1 μg/mL, respectively. NZ was found highly susceptible to nitrosation in SGJ reaching 100% nitrosation in 10 min, while only 18% nitrosation was observed after 160 min under the WHO-suggested conditions. The chemical structure of NZ-NO was clarified by ESI+/MS. In silico toxicology study confirmed the mutagenicity and toxicity of NZ-NO. Experiments evidenced that ascorbic acid strongly suppresses the nitrosation of NZ suggesting their co-administration for protection from potential risks. In addition, the impacts of the HILIC method on safety, health, and environment were favorably evaluated by three green analytical chemistry metrics and it was proved that, unlike the popular impression, HILIC methods could be green to the environment.
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Affiliation(s)
- Rania El-Shaheny
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Hygienic Chemistry and Toxicology, Course of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
| | - Mohamed Radwan
- Department of Drug Discovery, Science Farm Ltd., 1-7-30 Kuhonji, Chuo-ku, Kumamoto 862-0976, Japan; Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University, 5-1 Oehonmachi, Chuo-ku, Kumamoto 862-0973, Japan; Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki 12622, Cairo, Egypt
| | - Koji Yamada
- Medical Plant Laboratory, Course of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
| | - Mahmoud El-Maghrabey
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Analytical Chemistry for Pharmaceuticals, Course of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
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30
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Thomsen AML, Liew Z, Riis AH, Stayner LT, Ramlau-Hansen CH, Sigsgaard T, Olsen J. Nitrosatable drug exposure during pregnancy and risk of stillbirth. Pharmacoepidemiol Drug Saf 2019; 28:1204-1210. [PMID: 31348585 DOI: 10.1002/pds.4867] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 05/19/2019] [Accepted: 07/03/2019] [Indexed: 11/06/2022]
Abstract
PURPOSE Nitrosatable drugs can react with nitrite in the stomach and form N-nitroso compounds. Exposure to nitrosatable drugs has been associated with congenital malformations and preterm birth, but use during pregnancy as a cause of fetal death is not well-known. We examined if prenatally nitrosatable drug use is associated with risk of stillbirth. METHODS A nationwide cohort was conducted using 554 844 women with singleton and first recorded pregnancies regardless of previous pregnancy history from the Danish Medical Birth Register from 1996 to 2015. Exposure was recorded by use of the Danish National Prescription Register and defined as women who had redeemed a prescribed nitrosatable drug in the first 22 weeks of pregnancy. The reference group was women with no redeemed prescribed nitrosatable drug in this time period. We categorized nitrosatable drugs as secondary amines, tertiary amines, and amides. Cox hazard regression was used to estimate crude and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for stillbirth. RESULTS Among the 84 720 exposed women, 348 had a stillbirth compared with 1690 stillbirths among the 470 124 unexposed women. Women who used any prescribed nitrosatable drug were more likely to have a stillbirth compared with unexposed women (aHRs 1.24; 95% CI, 1.03-1.49). CONCLUSION Nitrosatable drug use during the first 22 weeks of pregnancy might increase risk of stillbirth. The findings should be interpreted cautiously because of important unmeasured factors that might influence the observed association, including maternal vitamin C intake, dietary, and other sources of nitrate/nitrite intake.
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Affiliation(s)
- Anne Marie L Thomsen
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Zeyan Liew
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA.,Yale Center for Perinatal, Pediatric, and Environmental Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | | | - Leslie Thomas Stayner
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA
| | | | - Torben Sigsgaard
- Department of Public Health, Section for Environment, Occupation, and Health, Aarhus University, Aarhus, Denmark
| | - Jørn Olsen
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
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Liu Q, Lei Z, Gu C, Guo J, Yu H, Fatima Z, Zhou K, Shabbir MAB, Maan MK, Wu Q, Xie S, Wang X, Yuan Z. Mequindox induces apoptosis, DNA damage, and carcinogenicity in Wistar rats. Food Chem Toxicol 2019; 127:270-279. [PMID: 30922968 DOI: 10.1016/j.fct.2019.03.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 03/10/2019] [Accepted: 03/12/2019] [Indexed: 12/18/2022]
Abstract
Mequindox (MEQ) is a synthetic antibacterial agent. Recent studies showed that MEQ and its primary metabolites exhibit strong genotoxicity to mammalian cells, and MEQ induced carcinogenicity in mice. These findings suggest that chronic exposure to MEQ could lead to an increased risk of cancer later in life. In the present study, four groups of Wistar rats (55 rats/sex/group) were fed with diets containing MEQ (0, 25, 55, and 110 mg/kg) for 2 years. The results showed that the hematological system, liver, kidneys, and adrenal glands, as well as the developmental and reproductive systems, were the main targets for MEQ. Liver toxicity mediated by MEQ was associated with apoptosis and the nuclear factor κB (NF-κB) signaling pathway. In addition, MEQ increased the incidence of tumors in rats. Phosphorylated histone H2AX (γ-H2AX) is identified as a biomarker of cellular response to DNA double-strand breaks (DSB). Our data demonstrated that γ-H2AX expression was significantly increased in tumors. Thus, high levels of DSB might be responsible for carcinogenesis in rats, and further investigation is absolutely required to clarify the exact molecular mechanisms for carcinogenicity caused by MEQ in vivo.
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Affiliation(s)
- Qianying Liu
- National Reference Laboratory of Veterinary Drug Residues (HZAU), MAO Key Laboratory for Detection of Veterinary Drug Residues, China
| | - Zhixin Lei
- Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA
| | - Changqin Gu
- A Department of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei, China
| | - Jingchao Guo
- MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Huiru Yu
- MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Zainab Fatima
- MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Kaixiang Zhou
- MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Muhammad A B Shabbir
- MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Muhammad Kashif Maan
- MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Qinghua Wu
- College of Life Science, Yangtze University, Jingzhou, China; Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Hradec Kralove, Czech Republic
| | - Shuyu Xie
- MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
| | - Xu Wang
- MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Zonghui Yuan
- National Reference Laboratory of Veterinary Drug Residues (HZAU), MAO Key Laboratory for Detection of Veterinary Drug Residues, China; MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
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32
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Kuyooro SE, Akintunde JK, Okekearu FC, Maduagwu EN. Toxicokinetics and Biliary Excretion of N-Nitrosodiethylamine in Rat Supplemented with Low and High Dietary Proteins. J Diet Suppl 2018; 16:506-520. [PMID: 30513225 DOI: 10.1080/19390211.2018.1471561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Although biliary excretion is one of the biological elimination processes for foreign compounds, intake of high-protein diets was hypothesized to enhance their detoxification rates. Hence, this study investigates the effect of differential dietary protein intake on toxicokinetics and biliary excretion in rats following exposure to N-nitrosodiethylamine (NDEA) and aflatoxin B1 (AFB1). The animals were divided into five groups. Groups I and II were exposed to low and high dietary proteins following a single intraperitoneal dose of 43 µg NDEA/kg body weight, respectively. Groups III and IV were equally treated after a combined single intraperitoneal dose of 43 µg NDEA plus 0.022µg AFBI/kg body weight, respectively. Group V was fed with low-protein diets following a single intraperitoneal dose of 0.022µg AFB1/kg body weight. The experiment lasted 35 days. The bile excreted higher amounts of unchanged NDEA than nitrite. The groups placed on high-protein diets (HPD = 64%) eliminated higher amounts of the unchanged NDEA and nitrite than the lower-protein diet (LPD = 8%) groups. Furthermore, the animals fed with high dietary protein (HPD = 64%) depicted short half-life with corresponding increase in elimination rate constant. The presence of AFB1 heightened the excretion of bound NDEA with AFB1 than NDEA only. Generally, this study advocates that N-nitrosodiethylamine and the corresponding metabolites follow hepatobiliary system potentiated by high intake of dietary proteins.
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Affiliation(s)
- S E Kuyooro
- Department of Chemical Sciences, Biochemistry unit, College of Natural and Applied Sciences, Bells University of Technology , Ota , Nigeria.,Nutritional Biochemistry Research Laboratory, Department of Biochemistry, College of Medicine, University of Ibadan , Ibadan , Nigeria
| | - J K Akintunde
- Applied Biochemistry and Molecular Toxicology Research Group, Department of Biochemistry College of Biological Sciences, Federal University of Agriculture , Abeokuta , Nigeria
| | - F C Okekearu
- Nutritional Biochemistry Research Laboratory, Department of Biochemistry, College of Medicine, University of Ibadan , Ibadan , Nigeria
| | - E N Maduagwu
- Nutritional Biochemistry Research Laboratory, Department of Biochemistry, College of Medicine, University of Ibadan , Ibadan , Nigeria
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33
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Wang Y, Cao W, Yin C, Zhuang Q, Ni Y. Nonenzymatic Amperometric Sensor for Nitrite Detection Based on a Nanocomposite Consisting of Nickel Hydroxide and Reduced Graphene Oxide. ELECTROANAL 2018. [DOI: 10.1002/elan.201800627] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Yong Wang
- College of ChemistryNanchang University Nanchang 330031, Jiangxi China
| | - Wei Cao
- College of ChemistryNanchang University Nanchang 330031, Jiangxi China
| | - Chang Yin
- College of ChemistryNanchang University Nanchang 330031, Jiangxi China
| | - Qianfen Zhuang
- College of ChemistryNanchang University Nanchang 330031, Jiangxi China
| | - Yongnian Ni
- College of ChemistryNanchang University Nanchang 330031, Jiangxi China
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34
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Ayabaktı S, Yavuz Kocaman A. Cytogenotoxic effects of venlafaxine hydrochloride on cultured human peripheral blood lymphocytes. Drug Chem Toxicol 2018; 43:192-199. [PMID: 30025480 DOI: 10.1080/01480545.2018.1486410] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The potential genotoxic effect of venlafaxine hydrochloride (venlafaxine), an antidepressant drug-active ingredient, was investigated by using in vitro chromosome aberrations (CAs) and cytokinesis-block micronucleus (CBMN) assays in human peripheral blood lymphocytes (PBLs). Mitotic index (MI) and cytokinesis-block proliferation index (CBPI) were also calculated to determine the cytotoxicity of this active drug. For this aim, the human PBLs were treated with 25, 50, and 100 µg/ml venlafaxine for 24 h and 48 h. The results of this study showed that venlafaxine significantly induced the formation of structural CA and MN for all concentrations (25, 50, and 100 µg/ml) and treatment periods (24 h and 48 h) when compared with the negative and the solvent control (except 25 µg/ml at 48 h for MN). In addition, the increases in the percentage of structural CA and MN were concentration-dependent for both treatment times. With regard to cell cycle kinetics, venlafaxine significantly decreased the MI at all concentrations, and also CBPI at the higher concentrations for both treatment times as compared to the control groups. The present results indicate for the first time that venlafaxine had significant clastogenic and cytotoxic effects at the tested concentrations (25, 50, and 100 µg/ml) in the human PBLs, in vitro; therefore, its excessive and careless use may pose a potential risk to human health.
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Affiliation(s)
- Selim Ayabaktı
- Basic and Applied Sciences Institute, Hatay Mustafa Kemal University, Hatay, Turkey
| | - Ayşe Yavuz Kocaman
- Department of Biology, Faculty of Sciences and Letters, Hatay Mustafa Kemal University, Hatay, Turkey
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35
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Liu Q, Lei Z, Wu Q, Huang D, Xie S, Wang X, Pan Y, Yuan Z. Mequindox Induced Genotoxicity and Carcinogenicity in Mice. Front Pharmacol 2018; 9:361. [PMID: 29692735 PMCID: PMC5902691 DOI: 10.3389/fphar.2018.00361] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 03/27/2018] [Indexed: 12/16/2022] Open
Abstract
Mequindox (MEQ), acting as an inhibitor of deoxyribonucleic acid (DNA) synthesis, is a synthetic heterocyclic N-oxides. To investigate the potential carcinogenicity of MEQ, four groups of Kun-Ming (KM) mice (50 mice/sex/group) were fed with diets containing MEQ (0, 25, 55, and 110 mg/kg) for one and a half years. The result showed adverse effects on body weights, feed consumption, hematology, serum chemistry, organ weights, relative organ weights, and incidence of tumors during most of the study period. Treatment-related changes in hematology, serum chemistry, relative weights and histopathological examinations revealed that the hematological system, liver, kidneys, and adrenal glands, as well as the developmental and reproductive system, were the main targets after MEQ administration. Additionally, MEQ significantly increased the frequency of micronucleated normochromatic erythrocytes in bone marrow cells of mice. Furthermore, MEQ increased the incidence of tumors, including mammary fibroadenoma, breast cancer, corticosuprarenaloma, haemangiomas, hepatocarcinoma, and pulmonary adenoma. Interestingly, the higher incidence of tumors was noted in M25 mg/kg group, the lowest dietary concentration tested, which was equivalent to approximately 2.25 and 1.72 mg/kg b.w./day in females and males, respectively. It was assumed that the lower toxicity might be a reason for its higher tumor incidence in M25 mg/kg group. This finding suggests a potential relationships among the dose, general toxicity and carcinogenicity in vivo, and further study is required to reveal this relationship. In conclusion, the present study demonstrates that MEQ is a genotoxic carcinogen in KM mice.
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Affiliation(s)
- Qianying Liu
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, China.,Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Huazhong Agricultural University, Wuhan, China
| | - Zhixin Lei
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, China
| | - Qin Wu
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, China
| | - Deyu Huang
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, China
| | - Shuyu Xie
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, China.,MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, China
| | - Xu Wang
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, China.,MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, China
| | - Yuanhu Pan
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, China.,MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, China
| | - Zonghui Yuan
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, China.,Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Huazhong Agricultural University, Wuhan, China.,MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, China.,Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, China
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Alzoubi KH, Bayraktar E, Khabour O, Al-Azzam SI. Vitamin B12 protects against DNA damage induced by hydrochlorothiazide. Saudi Pharm J 2018; 26:786-789. [PMID: 30202218 PMCID: PMC6128724 DOI: 10.1016/j.jsps.2018.04.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Accepted: 04/02/2018] [Indexed: 12/14/2022] Open
Abstract
DNA damage induced by hydrochlorothiazide was previously reported in cultured human lymphocytes. In this study, we aimed to investigate the harmful effects of hydrochlorothiazide on DNA by measuring the spontaneous frequency of sister chromatid exchanges (SCEs) in cultured human lymphocytes. We also aimed to investigate the possible protection of that damage by vitamin B12. The results showed that hydrochlorothiazide (5 µg/mL) significantly increased the frequency of sister chromatid exchanges (P < 0.001) in human lymphocytes in comparison with control. Additionally, the frequency of hydrochlorothiazide-induced SCEs was significantly decreased by co-treatment with vitamin B12 at concentration of 13.5 µg/mL (P < 0.001). In conclusion, hydrochlorothiazide is genotoxic to human lymphocytes and its toxicity is reduced by vitamin B12.
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Affiliation(s)
- Karem H Alzoubi
- Department of Clinical Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Erva Bayraktar
- Department of Clinical Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Omar Khabour
- Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan
| | - Sayer I Al-Azzam
- Department of Clinical Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
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Liu Q, Lei Z, Zhu F, Ihsan A, Wang X, Yuan Z. A Novel Strategy to Predict Carcinogenicity of Antiparasitics Based on a Combination of DNA Lesions and Bacterial Mutagenicity Tests. Front Public Health 2017; 5:288. [PMID: 29170735 PMCID: PMC5684118 DOI: 10.3389/fpubh.2017.00288] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 10/16/2017] [Indexed: 11/13/2022] Open
Abstract
Genotoxicity and carcinogenicity testing of pharmaceuticals prior to commercialization is requested by regulatory agencies. The bacterial mutagenicity test was considered having the highest accuracy of carcinogenic prediction. However, some evidences suggest that it always results in false-positive responses when the bacterial mutagenicity test is used to predict carcinogenicity. Along with major changes made to the International Committee on Harmonization guidance on genotoxicity testing [S2 (R1)], the old data (especially the cytotgenetic data) may not meet current guidelines. This review provides a compendium of retrievable results of genotoxicity and animal carcinogenicity of 136 antiparasitics. Neither genotoxicity nor carcinogenicity data is available for 84 (61.8%), while 52 (38.2%) have been evaluated in at least one genotoxicity or carcinogenicity study, and only 20 (14.7%) in both genotoxicity and carcinogenicity studies. Among 33 antiparasitics with at least one old result in in vitro genotoxicity, 15 (45.5%) are in agreement with the current ICH S2 (R1) guidance for data acceptance. Compared with other genotoxicity assays, the DNA lesions can significantly increase the accuracy of prediction of carcinogenicity. Together, a combination of DNA lesion and bacterial tests is a more accurate way to predict carcinogenicity.
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Affiliation(s)
- Qianying Liu
- MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, China
| | - Zhixin Lei
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Wuhan, China
| | - Feng Zhu
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Wuhan, China
| | - Awais Ihsan
- Department of Biosciences, COMSATS Institute of Information Technology, Sahiwal, Pakistan
| | - Xu Wang
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, China
| | - Zonghui Yuan
- MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, China
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Wuhan, China
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, China
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38
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Wei F, Jiang X, Gao HY, Gao SH. Liquiritin induces apoptosis and autophagy in cisplatin (DDP)-resistant gastric cancer cells in vitro and xenograft nude mice in vivo. Int J Oncol 2017; 51:1383-1394. [PMID: 29048624 PMCID: PMC5642394 DOI: 10.3892/ijo.2017.4134] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Accepted: 07/20/2017] [Indexed: 02/04/2023] Open
Abstract
Gastric cancer is reported as one of the leading factors resulting in tumor-related death worldwide. However, the therapies to suppress gastric cancer are still limited and the emergence of drug resistance makes it necessary to develop new and effective anticancer drugs and combinational chemotherapy schemes. Liquiritin (LIQ) is a major constituent of Glycyrrhiza Radix, exhibiting various pharmacological activities, including anticancer. In this study, we investigated the role of LIQ in human gastric cancer cells with cisplatin (DDP) resistance. The findings suggested that LIQ, when applied in single therapy, could moderately inhibit the proliferation and migration of DDP-resistant gastric cancer cells, SGC7901/DDP. DDP and LIQ in combination induced G0/G1 cell cycle arrest to suppress the proliferation of gastric cancer cells, which were associated with the decrease of cyclin D1, cyclin A and cyclin-dependent kinase 4 (CDK4) and increase of p53 and p21. In addition, LIQ combined with DDP significantly induce apoptosis and autophagy both in vitro and in vivo through enhancing cleavage of caspase-8/-9/-3 and PARP, as well as LC3B and Beclin 1 expression. Significantly, the two drugs, when used in combination, prevented gastric cancer cell xenografts in nude mice in vivo. Together, the results revealed that application of DDP and LIQ in combination possessed a potential value against the growth of human gastric cancer with DDP resistance.
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Affiliation(s)
- Feng Wei
- Department of Hepatobiliary and Pancreas Surgery, First Hospital of Jilin University
| | - Xin Jiang
- Department of Biochemistry, Basic College of Medicine, Jilin University
| | - Hao-Yue Gao
- Basic College of Medicine, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Shuo-Hui Gao
- Department of Gastrointestinal Colorectal Surgery, China-Japan Union Hospital of Jilin University
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39
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Ansari FA, Ali SN, Mahmood R. Crocin protects human erythrocytes from nitrite-induced methemoglobin formation and oxidative damage. Cell Biol Int 2016; 40:1320-1331. [DOI: 10.1002/cbin.10687] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 09/26/2016] [Indexed: 11/07/2022]
Affiliation(s)
- Fariheen Aisha Ansari
- Faculty of Life Sciences, Department of Biochemistry; Aligarh Muslim University; Aligarh Uttar Pradesh 202002 India
| | - Shaikh Nisar Ali
- Faculty of Life Sciences, Department of Biochemistry; Aligarh Muslim University; Aligarh Uttar Pradesh 202002 India
| | - Riaz Mahmood
- Faculty of Life Sciences, Department of Biochemistry; Aligarh Muslim University; Aligarh Uttar Pradesh 202002 India
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40
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Ansari FA, Mahmood R. Sodium nitrite enhances generation of reactive oxygen species that decrease antioxidant power and inhibit plasma membrane redox system of human erythrocytes. Cell Biol Int 2016; 40:887-94. [PMID: 27214747 DOI: 10.1002/cbin.10628] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 05/20/2016] [Indexed: 02/07/2023]
Abstract
Nitrite/nitrate salts are used in fertilizers and as food preservatives. Human exposure to high levels of nitrite results in its uptake and subsequent entry into blood where it can interact with erythrocytes. We show that treatment of human erythrocytes with sodium nitrite (NaNO2 ) results in a dose-dependent increase in the production of reactive oxygen species. This was accompanied by a decrease in the antioxidant power which lowered the free radical quenching and metal-reducing ability. NaNO2 treatment also inhibited plasma membrane redox system (PMRS) of erythrocytes. These changes increase the susceptibility of erythrocytes to oxidative damage, decrease the antioxidant power of whole blood, and can be a major cause of nitrite-induced cellular toxicity.
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Affiliation(s)
- Fariheen Aisha Ansari
- Faculty of Life Sciences, Department of Biochemistry, Aligarh Muslim University, Aligarh, 202002,, Uttar Pradesh, India
| | - Riaz Mahmood
- Faculty of Life Sciences, Department of Biochemistry, Aligarh Muslim University, Aligarh, 202002,, Uttar Pradesh, India
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41
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Hou S, Xian L, Shi P, Li C, Lin Z, Gao X. The Magea gene cluster regulates male germ cell apoptosis without affecting the fertility in mice. Sci Rep 2016; 6:26735. [PMID: 27226137 PMCID: PMC4880894 DOI: 10.1038/srep26735] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 05/06/2016] [Indexed: 11/21/2022] Open
Abstract
While apoptosis is essential for male germ cell development, improper activation of apoptosis in the testis can affect spermatogenesis and cause reproduction defects. Members of the MAGE-A (melanoma antigen family A) gene family are frequently clustered in mammalian genomes and are exclusively expressed in the testes of normal animals but abnormally activated in a wide variety of cancers. We investigated the potential roles of these genes in spermatogenesis by generating a mouse model with a 210-kb genomic deletion encompassing six members of the Magea gene cluster (Magea1, Magea2, Magea3, Magea5, Magea6 and Magea8). Male mice carrying the deletion displayed smaller testes from 2 months old with a marked increase in apoptotic germ cells in the first wave of spermatogenesis. Furthermore, we found that Magea genes prevented stress-induced spermatogenic apoptosis after N-ethyl-N-nitrosourea (ENU) treatment during the adult stage. Mechanistically, deletion of the Magea gene cluster resulted in a dramatic increase in apoptotic germ cells, predominantly spermatocytes, with activation of p53 and induction of Bax in the testes. These observations demonstrate that the Magea genes are crucial in maintaining normal testicular size and protecting germ cells from excessive apoptosis under genotoxic stress.
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Affiliation(s)
- Siyuan Hou
- State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, China
| | - Li Xian
- State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, China
| | - Peiliang Shi
- State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, China
| | - Chaojun Li
- State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, China
| | - Zhaoyu Lin
- State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, China
| | - Xiang Gao
- State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, China
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42
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Liu Q, Zhang J, Luo X, Ihsan A, Liu X, Dai M, Cheng G, Hao H, Wang X, Yuan Z. Further investigations into the genotoxicity of quinoxaline-di-N-oxides and their primary metabolites. Food Chem Toxicol 2016; 93:145-57. [PMID: 27170491 DOI: 10.1016/j.fct.2016.04.029] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 04/26/2016] [Accepted: 04/28/2016] [Indexed: 12/15/2022]
Abstract
Quinoxaline-di-N-oxides (QdNOs) are potential antibacterial agents with a wide range of biological properties. Quinocetone (QCT), carbadox (CBX), olaquindox (OLA), mequindox (MEQ) and cyadox (CYA) are classical QdNOs. Though the genotoxicity of parent drugs has been evaluated, the genotoxicity of their primary N → O reduced metabolites remains unclear. In the present study, a battery of four different short-term tests, mouse lymphoma assay (MLA), Ames test, chromosomal aberration assay in vitro and bone marrow erythrocyte micronucleus assay in vivo was carried out to investigate the genotoxicity of the six primary N → O reduced metabolites. Additionally, the genotoxicity of five parent drugs was evaluated by the MLA. Strong genotoxicity of N1-MEQ, B-MEQ and B-CBX was found in three of the assays but not in the Ames assay, and the rank order was N1-MEQ>B-MEQ>B-CBX that is consistent with prototype QdNOs. Negative results for the five QdNOs were noted in the MLA. We present for the first time a comparison of the genotoxicity of primary N → O reduced metabolites, and evaluate the ability of five QdNOs to cause mutations in the MLA. The present study demonstrates that metabolites are involved in genetic toxicity mediated by QdNOs, and improve the prudent use of QdNOs for public health.
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Affiliation(s)
- Qianying Liu
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Jianwu Zhang
- MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Xun Luo
- MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Awais Ihsan
- Department of Biosciences, COMSATS Institute of Information Technology, Sahiwal, Pakistan
| | - Xianglian Liu
- MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Menghong Dai
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China
| | - Guyue Cheng
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China
| | - Haihong Hao
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China
| | - Xu Wang
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China.
| | - Zonghui Yuan
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei 430070, China; MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China; Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China.
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Vuong AM, Shinde MU, Brender JD, Shipp EM, Huber JC, Sharkey JR, McDonald TJ, Werler MM, Kelley KE, Griesenbeck JS, Langlois PH, Canfield MA. Prenatal Exposure to Nitrosatable Drugs, Dietary Intake of Nitrites, and Preterm Birth. Am J Epidemiol 2016; 183:634-42. [PMID: 26953287 DOI: 10.1093/aje/kwv250] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Accepted: 09/08/2015] [Indexed: 02/01/2023] Open
Abstract
Prenatal exposure to nitrosatable drugs, including secondary or tertiary amines, has been associated with preterm birth. Associations may be accentuated by higher intakes of dietary nitrites because of the increased formation of N-nitroso compounds. Using data from mothers of babies without major birth defects (controls) from the National Birth Defects Prevention Study, we examined the relationship between nitrosatable drug exposure in conjunction with dietary nitrite intake and preterm birth among 496 mothers of preterm infants and 5,398 mothers with full-term deliveries in 1997-2005. A protective association was observed with a high intake of plant nitrites (adjusted hazard ratio (AHR) = 0.72, 95% confidence interval (CI): 0.53, 0.97). Secondary amines in conjunction with high nitrite intake were associated with preterm birth during the first (AHR = 1.84, 95% CI: 1.14, 2.98), second (AHR = 1.89, 95% CI: 1.17, 3.07), and third (AHR = 2.00, 95% CI: 1.22, 3.29) trimesters. The adjusted hazard ratios for tertiary amine use in the third trimester by increasing tertiles of nitrite intake were 0.67 (95% CI: 0.35, 1.31), 1.25 (95% CI: 0.71, 2.19), and 2.02 (95% CI: 1.17, 3.49). Prenatal exposure to nitrosatable drugs, particularly secondary and tertiary amines, in conjunction with higher levels of dietary nitrite intake may increase the risk of preterm birth.
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Zeng T, Mitch WA. Contribution of N-Nitrosamines and Their Precursors to Domestic Sewage by Greywaters and Blackwaters. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2015; 49:13158-67. [PMID: 26496512 DOI: 10.1021/acs.est.5b04254] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
N-nitrosamines and their precursors are significant concerns for water utilities exploiting wastewater-impacted water supplies, particularly those practicing potable reuse of wastewater. Previous efforts to identify specific precursors in municipal wastewater accounting for N-nitrosamine formation have met with limited success. As an alternative, we quantified the relative importance of greywater (i.e., shower, kitchen sink, bathroom washbasin, and laundry) and blackwater (i.e., urine and feces) streams in terms of their loadings of ambient specific and total N-nitrosamines and chloramine-reactive and ozone-reactive N-nitrosamine precursors to domestic sewage. Accounting for the volume fractions of individual greywater and blackwater streams, laundry water represented the most significant source of N-nitrosamines and their precursors, followed by shower water and urine. Laundry water was particularly important for ozone-reactive N-nitrosamine precursors, accounting for ∼99% of N-nitrosodimethylamine (NDMA) precursors and ∼69% of precursors for other uncharacterized N-nitrosamines. For the other greywater streams, consumer products contributed additional N-nitrosamines and precursors, but the remarkable uniformity across different products suggested the importance of common macroconstituents. The consumption of a standard dose of the antacid ranitidine substantially increased NDMA and its chloramine-reactive precursors in urine. Nevertheless, nearly 40% of the American population would need to consume ranitidine daily to match the NDMA loadings from laundry water.
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Affiliation(s)
- Teng Zeng
- Department of Civil and Environmental Engineering, Stanford University , 473 Via Ortega, Stanford, California 94305, United States
- National Science Foundation Engineering Research Center for Re-Inventing the Nation's Urban Water Infrastructure (ReNUWIt) , 473 Via Ortega, Stanford, California 94305, United States
| | - William A Mitch
- Department of Civil and Environmental Engineering, Stanford University , 473 Via Ortega, Stanford, California 94305, United States
- National Science Foundation Engineering Research Center for Re-Inventing the Nation's Urban Water Infrastructure (ReNUWIt) , 473 Via Ortega, Stanford, California 94305, United States
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Ansari FA, Ali SN, Mahmood R. Sodium nitrite-induced oxidative stress causes membrane damage, protein oxidation, lipid peroxidation and alters major metabolic pathways in human erythrocytes. Toxicol In Vitro 2015; 29:1878-86. [DOI: 10.1016/j.tiv.2015.07.022] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Revised: 07/02/2015] [Accepted: 07/27/2015] [Indexed: 01/07/2023]
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Kudrnáčová E, Kouřimská L. Qualitative parameters of non-traditional types of vegetables. POTRAVINARSTVO 2015. [DOI: 10.5219/466] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The main aim of this study was to determine selected quality indicators of non-traditional types of leafy vegetables. Mizuna (Brassica rapa japonica), Chinese mustard (Brassica juncea), edible chrysanthemum (Chrysanthemum coronarium) and arugula (Eruca sativa) belonged among the selected species of vegetables. During the one-year experiment, spring and autumn sowing was carried out for these species of vegetables. The measured quality parameters were the content of nitrates and ascorbic acid. Sampling was done in the morning and in the laboratory, the samples were further processed according to the type of determination. To determine the content of nitrates and ascorbic acid, leaves were removed from plants. The filtrate from the leaves was then prepared. Determination of nitrates and ascorbic acid was carried out using a special test strip and device Rqflex plus 10. The results of measurement of both sowing varieties were compared. Total nitrate content was higher up to 22% in plants sown in the autumn except edible chrysanthemum (Chrysanthemum coronarium). The highest content was recorded in arugula (Eruca sativa), which was recently implemented to the studies of the European Union and for which there were set the limits of nitrates. Overall, the nitrate content ranged from 221 to 334 ppm in spring varieties and from 249 to 384 mg/kg in autumn varieties. Ascorbic acid content was very high in Chinese mustard (Brassica juncea), edible chrysanthemum (Chrysanthemum coronarium) and arugula (Eruca sativa) in both spring and autumn varieties. Values of ascorbic acid ranged from 839 in autumn sowing up to 2909 mg/kg in spring sowing. These non-traditional types of leafy vegetables could be included among the other importants sources of vitamin C in the future.
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Omura K, Uehara T, Morikawa Y, Hayashi H, Mitsumori K, Minami K, Kanki M, Yamada H, Ono A, Urushidani T. Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model. J Toxicol Sci 2015; 39:837-48. [PMID: 25374375 DOI: 10.2131/jts.39.837] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Recent studies have shown that epigenetic alterations correlate with carcinogenesis in various tissues. Identification of these alterations might help characterize the early stages of carcinogenesis. We comprehensively analyzed DNA methylation and gene expression in livers obtained from rats exposed to nitrosodiethylamine (DEN) followed by a promoter of hepatic carcinogenesis, phenobarbital (PB). The combination of DEN and PB induced marked increases in number and area of glutathione S-transferase-placental form (GST-P)-positive foci in the liver. In the liver of rats that received 30 mg/kg of DEN, pathway analysis revealed alterations of common genes in terms of gene expression and DNA methylation, and that these alterations were related to immune responses. Hierarchical clustering analysis of the expression of common genes from public data obtained through the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system (TG-GATEs) showed that carcinogenic compounds clustered together. MBD-seq and GeneChip analysis indicated that major histocompatibility complex class Ib gene RT1-CE5, which has an important role in antigen presentation, was hypomethylated around the promoter region and specifically induced in the livers of DEN-treated rats. Further, immunohistochemical analysis indicated that the co-localization of GST-P and protein homologous to RT1-CE5 was present at the foci of some regions. These results suggest that common genes were altered in terms of both DNA methylation and expression in livers, with preneoplastic foci indicating carcinogenic potential, and that immune responses are involved in early carcinogenesis. In conclusion, the present study identified a specific profile of DNA methylation and gene expression in livers with preneoplastic foci. Early epigenetic perturbations of immune responses might correlate with the early stages of hepatocarcinogenesis.
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Affiliation(s)
- Ko Omura
- Drug Safety Research Laboratories, Astellas Pharma Inc
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Vuong AM, Shinde MU, Brender JD, Shipp EM, Huber JC, Zheng Q, McDonald TJ, Sharkey JR, Hoyt AT, Werler MM, Kelley KE, Langlois PH, Canfield MA. Nitrosatable Drug Exposure during Pregnancy and Preterm and Small-for-Gestational-Age Births. Paediatr Perinat Epidemiol 2015; 29:60-71. [PMID: 25492517 DOI: 10.1111/ppe.12169] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Nitrosatable drugs react with nitrite in the stomach to form N-nitroso compounds, observed in animal models to result in adverse pregnancy outcomes, such as birth defects and reduced fetal weight. Previous studies examining prenatal exposure to medications classified as nitrosatable have reported an increased risk of preterm births (PTBs) and small-for-gestational-age (SGA) infants. METHODS Using data from mothers (controls) of babies without major birth defects from the National Birth Defects Prevention Study, prenatal nitrosatable drug usage by trimester and month of gestation was examined in relation to PTBs and SGA infants. RESULTS Positive associations were observed with nitrosatable drug use and PTBs, with the strongest relationship with second trimester exposure (adjusted hazard ratio [aHR] 1.37, [95% confidence interval (CI) 1.10, 1.70]). Of the nitrosatable functional groups, secondary amines were the most notable, with a higher association among women with second (aHR 1.37, [95% CI 1.05, 1.79]) and third (aHR 1.34, [95% CI 1.02, 1.76]) trimester exposure compared with women with no prenatal nitrosatable drug use. Among SGA infants, a borderline association was noted with amide exposure during the third trimester (adjusted odds ratio 1.43 [95% confidence interval [CI] 1.00, 2.05]). CONCLUSIONS Prenatal exposure to nitrosatable drugs during the second and third trimester of pregnancy, particularly secondary amines, might increase the risk of PTBs. However, prenatal exposure to nitrosatable drugs was not associated with SGA infants, with the exception of amide drugs.
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Affiliation(s)
- Ann M Vuong
- Division of Epidemiology, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH
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Dutta R, Ghosh P. Artificial receptors for nitrate: a comprehensive overview. Chem Commun (Camb) 2015; 51:9070-84. [DOI: 10.1039/c5cc01266j] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
In this feature article, we describe the current status and recent development of synthetic anion receptors for the recognition of nitrate.
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Affiliation(s)
- Ranjan Dutta
- Department of Inorganic Chemistry
- Indian Association for the Cultivation of Science
- Kolkata-700032
- India
| | - Pradyut Ghosh
- Department of Inorganic Chemistry
- Indian Association for the Cultivation of Science
- Kolkata-700032
- India
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Regulska K, Murias M, Stanisz B, Regulski M. The mutagenicity analysis of imidapril hydrochloride and its degradant, diketopiperazine derivative, nitrosation mixtures by in vitro Ames test with two strains of Salmonella typhimurium. Rep Pract Oncol Radiother 2014; 19:412-9. [PMID: 25337415 DOI: 10.1016/j.rpor.2014.04.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/09/2014] [Accepted: 04/05/2014] [Indexed: 12/30/2022] Open
Abstract
AIM The evaluation of mutagenic properties of imidapril hydrochloride (IMD) and its degradation impurity, diketopiperazine derivative (DKP), nitrosation mixtures was conducted in order to analyze the carcinogenic risk of IMD long-term treatment in patients. In this study an in vitro Ames test with Salmonella enterica serovar Typhimurium TA 98 and TA 100 strains was used. BACKGROUND IMD and DKP contain nitrogen atoms, which makes them theoretically vulnerable to in vivo nitrosation with the production of N-nitroso compounds (NOC). NOC, in turn, are known animal mutagens indicating that their endogenous production from nitrosable drugs constitutes a carcinogenic hazard. MATERIALS AND METHODS Pure IMD sample was exposed to forced degradation conditions of increased temperature and dry air in order to achieve a DKP sample. Both samples were then treated with a nitrosating agent and the obtained nitrosation mixtures were subjected to mutagenicity analysis by the Ames test with S. typhimurium TA 98 and TA 100 strains in the presence and absence of metabolic activation system (S9 mix) using a commercial Ames MPF 98/100 microplate format mutagenicity assay kit. RESULTS None of the six concentrations of the investigated nitrosation mixtures exhibited any mutagenic potential in both S. typhimurium strains. The addition of S9 mix did not alter the non-mutagenic properties of the studied compounds. CONCLUSIONS The nitrite treatment of both studied compounds has no impact on their mutagenic properties under the conditions of the present studies. Hence, IMD and DKP nitrosation mixtures are classified as non-mutagens in this test.
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Affiliation(s)
- Katarzyna Regulska
- Greater Poland Cancer Center, 15th Garbary Street, 61-866 Poznan, Poland ; Poznan University of Medical Sciences, Chair and Department of Pharmaceutical Chemistry, 6th Grunwaldzka Street, 60-780 Poznan, Poland
| | - Marek Murias
- Poznan University of Medical Sciences, Chair and Department of Toxicology, 30th Dojazd Street, 60-631 Poznan, Poland
| | - Beata Stanisz
- Poznan University of Medical Sciences, Chair and Department of Pharmaceutical Chemistry, 6th Grunwaldzka Street, 60-780 Poznan, Poland
| | - Miłosz Regulski
- Poznan University of Medical Sciences, Chair and Department of Toxicology, 30th Dojazd Street, 60-631 Poznan, Poland
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