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CYP2E1, GSTM1 and GSTT1 genetic polymorphisms and susceptibility to antituberculosis drug-induced hepatotoxicity: a nested case-control study.
J Clin Pharm Ther. 2012 Oct; 37(5):588-93.JC

Abstract

WHAT IS KNOWN AND OBJECTIVE

The pathogenic mechanism of antituberculosis drug-induced hepatotoxicity (ATDH) is thought to involve drug-metabolizing enzymes including N-acetyl transferase2 (NAT2), cytochrome P4502E1 (CYP2E1) and glutathione S-transferase (GST) M1, T1. The associations between genetic polymorphisms of those genes and ATDH have been reported but with inconsistent results. Moreover, most studies were hospital-based retrospective studies and not prospective. We aimed to investigate possible associations of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms with ATDH using a more robust case-control study nested in a population-based prospective antituberculosis treatment cohort.

METHODS

A total of 4304 patients with smear-positive tuberculosis (TB) who received standard short-course chemotherapy were monitored for 6-9 months. Incidence density sampling method was adopted to select controls and 4 : 1 matched with each ATDH cases by age (± 5 years), sex, treatment history, disease severity and drug dosage. The CYP2E1, GSTM1 and GSTT1 polymorphisms were genotyped using PCR-RFLP and multiplex PCR methods. Conditional logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P-values.

RESULTS AND DISCUSSION

A total of 89 ATDH cases and 356 controls were included in this study. There was no statistically significant association between CYP2E1 RsaI c1/c1 genotype or DraI C/C genotype and ATDH (OR = 0·99, 95% CI:0·62-1·59; OR = 1·13, 95% CI: 0·40-3·20, respectively) compared with CYP2E1 RsaI c1/c2 or c2/c2 genotypes or DraI D/D genotype, or between GSTM1/GSTT1 null genotypes and ATDH (OR = 1·22, 95% CI: 0·76-1·96; OR = 0·96, 95% CI: 0·60-1·52, respectively) compared with non-null genotypes.

WHAT IS NEW AND CONCLUSION

This is the first study of the involvement of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms in ATDH using a nested case-control population-based prospective cohort design. We could not confirm positive associations of genetic polymorphisms of CYP2E1 RsaI, CYP2E1 DraI, GSTM1 null and GSTT1 null with ATDH reported by various groups, in our Chinese TB population.

Authors+Show Affiliations

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22335459

Citation

Tang, S-W, et al. "CYP2E1, GSTM1 and GSTT1 Genetic Polymorphisms and Susceptibility to Antituberculosis Drug-induced Hepatotoxicity: a Nested Case-control Study." Journal of Clinical Pharmacy and Therapeutics, vol. 37, no. 5, 2012, pp. 588-93.
Tang SW, Lv XZ, Zhang Y, et al. CYP2E1, GSTM1 and GSTT1 genetic polymorphisms and susceptibility to antituberculosis drug-induced hepatotoxicity: a nested case-control study. J Clin Pharm Ther. 2012;37(5):588-93.
Tang, S. W., Lv, X. Z., Zhang, Y., Wu, S. S., Yang, Z. R., Xia, Y. Y., Tu, D. H., Deng, P. Y., Ma, Y., Chen, D. F., & Zhan, S. Y. (2012). CYP2E1, GSTM1 and GSTT1 genetic polymorphisms and susceptibility to antituberculosis drug-induced hepatotoxicity: a nested case-control study. Journal of Clinical Pharmacy and Therapeutics, 37(5), 588-93. https://doi.org/10.1111/j.1365-2710.2012.01334.x
Tang SW, et al. CYP2E1, GSTM1 and GSTT1 Genetic Polymorphisms and Susceptibility to Antituberculosis Drug-induced Hepatotoxicity: a Nested Case-control Study. J Clin Pharm Ther. 2012;37(5):588-93. PubMed PMID: 22335459.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CYP2E1, GSTM1 and GSTT1 genetic polymorphisms and susceptibility to antituberculosis drug-induced hepatotoxicity: a nested case-control study. AU - Tang,S-W, AU - Lv,X-Z, AU - Zhang,Y, AU - Wu,S-S, AU - Yang,Z-R, AU - Xia,Y-Y, AU - Tu,D-H, AU - Deng,P-Y, AU - Ma,Y, AU - Chen,D-F, AU - Zhan,S-Y, Y1 - 2012/02/15/ PY - 2012/2/17/entrez PY - 2012/2/18/pubmed PY - 2013/4/4/medline SP - 588 EP - 93 JF - Journal of clinical pharmacy and therapeutics JO - J Clin Pharm Ther VL - 37 IS - 5 N2 - WHAT IS KNOWN AND OBJECTIVE: The pathogenic mechanism of antituberculosis drug-induced hepatotoxicity (ATDH) is thought to involve drug-metabolizing enzymes including N-acetyl transferase2 (NAT2), cytochrome P4502E1 (CYP2E1) and glutathione S-transferase (GST) M1, T1. The associations between genetic polymorphisms of those genes and ATDH have been reported but with inconsistent results. Moreover, most studies were hospital-based retrospective studies and not prospective. We aimed to investigate possible associations of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms with ATDH using a more robust case-control study nested in a population-based prospective antituberculosis treatment cohort. METHODS: A total of 4304 patients with smear-positive tuberculosis (TB) who received standard short-course chemotherapy were monitored for 6-9 months. Incidence density sampling method was adopted to select controls and 4 : 1 matched with each ATDH cases by age (± 5 years), sex, treatment history, disease severity and drug dosage. The CYP2E1, GSTM1 and GSTT1 polymorphisms were genotyped using PCR-RFLP and multiplex PCR methods. Conditional logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P-values. RESULTS AND DISCUSSION: A total of 89 ATDH cases and 356 controls were included in this study. There was no statistically significant association between CYP2E1 RsaI c1/c1 genotype or DraI C/C genotype and ATDH (OR = 0·99, 95% CI:0·62-1·59; OR = 1·13, 95% CI: 0·40-3·20, respectively) compared with CYP2E1 RsaI c1/c2 or c2/c2 genotypes or DraI D/D genotype, or between GSTM1/GSTT1 null genotypes and ATDH (OR = 1·22, 95% CI: 0·76-1·96; OR = 0·96, 95% CI: 0·60-1·52, respectively) compared with non-null genotypes. WHAT IS NEW AND CONCLUSION: This is the first study of the involvement of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms in ATDH using a nested case-control population-based prospective cohort design. We could not confirm positive associations of genetic polymorphisms of CYP2E1 RsaI, CYP2E1 DraI, GSTM1 null and GSTT1 null with ATDH reported by various groups, in our Chinese TB population. SN - 1365-2710 UR - https://www.unboundmedicine.com/medline/citation/22335459/CYP2E1_GSTM1_and_GSTT1_genetic_polymorphisms_and_susceptibility_to_antituberculosis_drug_induced_hepatotoxicity:_a_nested_case_control_study_ L2 - https://doi.org/10.1111/j.1365-2710.2012.01334.x DB - PRIME DP - Unbound Medicine ER -