GSTT1/GSTM1 Genotype and Anti-Tuberculosis Drug-Induced Hepatotoxicity in Peruvian Patients

Abstract

In Peru, 24,581 people were diagnosed with tuberculosis (TB) in 2020. Although TB treatments are effective, 3.4-13% are associated with significant adverse drug reactions (ADRs), with drug-induced liver injury (DILI) considered the most predominant. Among the first-line antituberculosis drugs, isoniazid (INH) is the main drug responsible for the appearance of DILI. In the liver, INH is metabolized by the enzymes N-acetyltransferase-2 (NAT2), cytochrome P450 2E1 (CYP2E1), and glutathione S-transferase (GST) with two isoforms, GSTT1 and GSTM1. Based on previous studies, we hypothesized that interactions between the <i>GSTT1</i> and <i>GSTM1</i> null genotypes induce DILI in TB patients. In this cross-sectional study of 377 participants who completed their anti-TB treatment, we genotyped by revealing the presence or absence of 215- and 480-bp bands of <i>GSTM1</i> and <i>GSTT1</i>, respectively. We found that the prevalence of the <i>GSTM1</i> genotype was 52.79% and 47.21% for presence and null, respectively, and for <i>GSTT1</i> it was 69.76% and 30.24% for presence and null, respectively. Neither genotype was prevalent in the patients who developed DILI (<i>n</i> = 16). We did not confirm our hypothesis; however, we found that the combination of <i>GSTM1</i> present genotype, <i>GSTT1</i> null genotype, fast <i>NAT2</i> acetylators, and <i>CYP2E1</i> c1/c1 genotype had a significant risk for the development of ADR (OR 11; <i>p</i> = 0.017; 95% CI: (0.54-186.35)). We propose that the presence of the <i>GSTM1</i> present genotype, <i>GSTT1</i> null genotype, fast <i>NAT2</i> acetylators, and <i>CYP2E1</i> c1/c1 genotype in the Peruvian population could be considered a risk factor for the development of ADR due to therapeutic drug intake.