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Evaluation of cytochrome P4502E1 polymorphisms in healthy adult Western Indians and patients with antituberculous drug-induced hepatotoxicity

OBJECTIVES: Cytochrome P4502E1 (CYP2E1) is involved in the metabolism of isoniazid and the mediation of its hepatotoxicity. It exhibits genetic polymorphism in humans. This study evaluated the polymorphism of CYP2E1 in adult healthy Western Indians and patients on antituberculous drugs by phenotypin...

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Autores principales: Gogtay, Nithya J., Kapileshwar, Swapnali R., Shah, Sanket U., Bendkhale, Shital R., Ramakrishna, Suresh, Sridharan, Kannan, Thelma, B. K., Thatte, Urmila M., Kshirsagar, Nilima A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Medknow Publications & Media Pvt Ltd 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778206/
https://www.ncbi.nlm.nih.gov/pubmed/26997721
http://dx.doi.org/10.4103/0253-7613.174519
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author Gogtay, Nithya J.
Kapileshwar, Swapnali R.
Shah, Sanket U.
Bendkhale, Shital R.
Ramakrishna, Suresh
Sridharan, Kannan
Thelma, B. K.
Thatte, Urmila M.
Kshirsagar, Nilima A.
author_facet Gogtay, Nithya J.
Kapileshwar, Swapnali R.
Shah, Sanket U.
Bendkhale, Shital R.
Ramakrishna, Suresh
Sridharan, Kannan
Thelma, B. K.
Thatte, Urmila M.
Kshirsagar, Nilima A.
author_sort Gogtay, Nithya J.
collection PubMed
description OBJECTIVES: Cytochrome P4502E1 (CYP2E1) is involved in the metabolism of isoniazid and the mediation of its hepatotoxicity. It exhibits genetic polymorphism in humans. This study evaluated the polymorphism of CYP2E1 in adult healthy Western Indians and patients on antituberculous drugs by phenotyping and genotyping. METHODS: A 500 mg single dose of chlorzoxazone (CZX) was administered to 136 healthy adult Western Indian participants. Venous blood samples 2 h postdose were analyzed for the levels of CZX and 6-hydroxy CZX, and the metabolic ratio (MR) was calculated to determine the extent of rapid and poor metabolizers using probit plot analysis. Patients on antituberculous drugs who had raised the liver enzymes or clinical symptoms of hepatotoxicity were also recruited. Genotyping for CYP2E1 * 5B allele was performed by polymerase chain reaction – rapid fragment length polymorphism technique. RESULTS: A total of 139 healthy participants were enrolled, of which the final analysis consisted of data from 136 participants for genotyping and 137 for phenotyping. Only 1 participant had reported mild drowsiness 2 h postdose, and no other adverse events were observed. The median (range) MR of population was 0.2 (0.1–4.0), and no polymorphisms were detected using phenotype data. A total of 134/136 (98.5%) had c1/c1 genotype and 1/136 each (0.75%) had c1/c2 and c2/c2 genotypes, respectively. Of the 2/136 participants harboring c2 allele, one had MR of 0.1 (c1/c2) and another had 0.5 (c2/c2). A total of 25 cases of antituberculous drug-induced hepatotoxicity and 50 control patients were recruited, of which finally 22 cases and 49 controls were available for evaluation. All the cases had c1/c1 genotype while 42/49 (85.7%) controls had c1/c1, 6/49 (12.2%) had c1/c2, and 1/49 (2.1%) had c2/c2 genotype and the crude odds ratio was 7.9 (0.4, 145.6). CONCLUSIONS: A background prevalence of CYP2E1*B polymorphism and their activity in Western Indian population was observed. The study suggests no association between the CYP2E1 genotyping with antituberculous drug-induced hepatotoxicity.
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spelling pubmed-47782062016-03-18 Evaluation of cytochrome P4502E1 polymorphisms in healthy adult Western Indians and patients with antituberculous drug-induced hepatotoxicity Gogtay, Nithya J. Kapileshwar, Swapnali R. Shah, Sanket U. Bendkhale, Shital R. Ramakrishna, Suresh Sridharan, Kannan Thelma, B. K. Thatte, Urmila M. Kshirsagar, Nilima A. Indian J Pharmacol Research Article OBJECTIVES: Cytochrome P4502E1 (CYP2E1) is involved in the metabolism of isoniazid and the mediation of its hepatotoxicity. It exhibits genetic polymorphism in humans. This study evaluated the polymorphism of CYP2E1 in adult healthy Western Indians and patients on antituberculous drugs by phenotyping and genotyping. METHODS: A 500 mg single dose of chlorzoxazone (CZX) was administered to 136 healthy adult Western Indian participants. Venous blood samples 2 h postdose were analyzed for the levels of CZX and 6-hydroxy CZX, and the metabolic ratio (MR) was calculated to determine the extent of rapid and poor metabolizers using probit plot analysis. Patients on antituberculous drugs who had raised the liver enzymes or clinical symptoms of hepatotoxicity were also recruited. Genotyping for CYP2E1 * 5B allele was performed by polymerase chain reaction – rapid fragment length polymorphism technique. RESULTS: A total of 139 healthy participants were enrolled, of which the final analysis consisted of data from 136 participants for genotyping and 137 for phenotyping. Only 1 participant had reported mild drowsiness 2 h postdose, and no other adverse events were observed. The median (range) MR of population was 0.2 (0.1–4.0), and no polymorphisms were detected using phenotype data. A total of 134/136 (98.5%) had c1/c1 genotype and 1/136 each (0.75%) had c1/c2 and c2/c2 genotypes, respectively. Of the 2/136 participants harboring c2 allele, one had MR of 0.1 (c1/c2) and another had 0.5 (c2/c2). A total of 25 cases of antituberculous drug-induced hepatotoxicity and 50 control patients were recruited, of which finally 22 cases and 49 controls were available for evaluation. All the cases had c1/c1 genotype while 42/49 (85.7%) controls had c1/c1, 6/49 (12.2%) had c1/c2, and 1/49 (2.1%) had c2/c2 genotype and the crude odds ratio was 7.9 (0.4, 145.6). CONCLUSIONS: A background prevalence of CYP2E1*B polymorphism and their activity in Western Indian population was observed. The study suggests no association between the CYP2E1 genotyping with antituberculous drug-induced hepatotoxicity. Medknow Publications & Media Pvt Ltd 2016 /pmc/articles/PMC4778206/ /pubmed/26997721 http://dx.doi.org/10.4103/0253-7613.174519 Text en Copyright: © Indian Journal of Pharmacology http://creativecommons.org/licenses/by-nc-sa/3.0 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
spellingShingle Research Article
Gogtay, Nithya J.
Kapileshwar, Swapnali R.
Shah, Sanket U.
Bendkhale, Shital R.
Ramakrishna, Suresh
Sridharan, Kannan
Thelma, B. K.
Thatte, Urmila M.
Kshirsagar, Nilima A.
Evaluation of cytochrome P4502E1 polymorphisms in healthy adult Western Indians and patients with antituberculous drug-induced hepatotoxicity
title Evaluation of cytochrome P4502E1 polymorphisms in healthy adult Western Indians and patients with antituberculous drug-induced hepatotoxicity
title_full Evaluation of cytochrome P4502E1 polymorphisms in healthy adult Western Indians and patients with antituberculous drug-induced hepatotoxicity
title_fullStr Evaluation of cytochrome P4502E1 polymorphisms in healthy adult Western Indians and patients with antituberculous drug-induced hepatotoxicity
title_full_unstemmed Evaluation of cytochrome P4502E1 polymorphisms in healthy adult Western Indians and patients with antituberculous drug-induced hepatotoxicity
title_short Evaluation of cytochrome P4502E1 polymorphisms in healthy adult Western Indians and patients with antituberculous drug-induced hepatotoxicity
title_sort evaluation of cytochrome p4502e1 polymorphisms in healthy adult western indians and patients with antituberculous drug-induced hepatotoxicity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778206/
https://www.ncbi.nlm.nih.gov/pubmed/26997721
http://dx.doi.org/10.4103/0253-7613.174519
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