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NAT2, CYP2C9, CYP2C19, and CYP2E1 genetic polymorphisms in anti-TB drug-induced maculopapular eruption

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

It has been suggested that drug-metabolizing enzymes might play important roles in the development of anti-tuberculosis drug (ATD)-induced maculopapular eruption (MPE), as in ATD-induced hepatitis. We investigated the associations between the genetic polymorphisms of drug-metabolizing enzymes and ATD-induced MPE.

Methods

We enrolled 62 patients with ATD-induced MPE (mean age 47.2 ± 19.0, male 59.7%) and 159 patients without any adverse reactions to ATD (mean age 42.8 ± 17.6, male 65.4%), among patients with pulmonary tuberculosis (TB) and/or TB pleuritis and treated with first-line anti-TB medications, including isoniazid, rifampin, ethambutol, and pyrazinamide. We compared the genotype distributions of single nucleotide polymorphisms and haplotypes in four drug-metabolizing enzymes (N-acetyltransferase 2 (NAT2), cytochrome P450 (CYP) 2 C9, CYP2C19, and CYP2E1) among patients with ATD-induced MPE and patients tolerant to ATD using a multivariate logistic regression analysis. These analyses were made without identification of the responsible ATD.

Results

−1565 C > T of CYP2C9 showed a significant association with ATD-induced MPE (P = 0.022, OR = 0.23, 95% CI 0.07–0.78), with a lower frequency of genotypes carrying minor alleles (CT or TT) in the case group than in the controls. Additionally, W212X of CYP2C19 was significantly associated with the risk of ATD-induced MPE (P = 0.042, OR = 0.27, 95% CI 0.09–0.82). In an analysis of the CYP2C19–CYP2C9 haplotypes (−1418 C > T_W212X_−1565 C > T_−1188 C > T), ht3[T-A-T-C] showed a significant association with the development of ATD-induced MPE (P = 0.012, OR = 0.13, 95% CI 0.03–0.57). No significant associations between the other genetic polymorphisms and ATD-induced MPE were observed.

Conclusions

CYP2C19 and CYP2C9 genetic polymorphisms are significantly associated with the risk of developing ATD-induced MPE, and the genetic variants in NAT2 and CYP2E1 are not closely related to the development of this adverse reaction.

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Acknowledgements

This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Korea (grant no. A030001).

Conflict of interest

None of the authors has any conflict of interest.

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Authors and Affiliations

  1. Department of Internal Medicine, Hanyang University College of Medicine, Haengdang-dong 17, Seongdong-gu, Seoul, Korea

    Sang-Heon Kim, Ho Joo Yoon, Dong Ho Shin & Sung Soo Park

  2. Department of Internal Medicine, Eulji University School of Medicine, Hagye-dong 280-1, Nowon-gu, Seoul, Korea

    Sang-Hoon Kim

  3. Department of Internal Medicine, Dankook University College of Medicine, Anseo-dong San 16-5, Cheonan, Korea

    Youn-Seup Kim, Jae-Seuk Park & Young Koo Jee

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  1. Sang-Heon Kim
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  2. Sang-Hoon Kim
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Correspondence to Young Koo Jee.

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Supplementary Table 1

Single nucleotide polymorphisms in the drug metabolism genes of healthy Koreans (DOC 109 kb)

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Kim, SH., Kim, SH., Yoon, H.J. et al. NAT2, CYP2C9, CYP2C19, and CYP2E1 genetic polymorphisms in anti-TB drug-induced maculopapular eruption. Eur J Clin Pharmacol 67, 121–127 (2011). https://doi.org/10.1007/s00228-010-0912-4

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  • DOI: https://doi.org/10.1007/s00228-010-0912-4

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