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

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.