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

• Published in: International journal of molecular sciences 2022-09, Vol.23 (19), p.11028
• Main Authors: Jaramillo-Valverde, Luis, Levano, Kelly S, Tarazona, David D, Vasquez-Dominguez, Andres, Toledo-Nauto, Anel, Capristano, Silvia, Sanchez, Cesar, Tarazona-Santos, Eduardo, Ugarte-Gil, Cesar, Guio, Heinner
• Format: Article
• Language: English
• Subjects: Acetyltransferase; Antitubercular Agents - adverse effects; Arylamine N-Acetyltransferase - genetics; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - genetics; Cross-Sectional Studies; Cytochrome P-450 CYP2E1 - genetics; Cytochrome P450; Cytochromes P450; Drugs; Enzymes; Genetic diversity; Genetic Predisposition to Disease; Genotype; Genotype & phenotype; Genotypes; Glutathione transferase; Glutathione Transferase - genetics; GSTM1; GSTM1 protein; GSTT1; GSTT1 protein; Hepatotoxicity; Humans; Isoforms; Isoniazid; Liver; Metabolites; Minority & ethnic groups; Mutation; N-Acetyltransferase 2; Patients; Peru - epidemiology; Polymorphism, Genetic; Population; Risk analysis; Risk factors; Tuberculosis; Tuberculosis - drug therapy; Tuberculosis - genetics; White people
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms231911028

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 and 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 and , respectively. We found that the prevalence of the genotype was 52.79% and 47.21% for presence and null, respectively, and for it was 69.76% and 30.24% for presence and null, respectively. Neither genotype was prevalent in the patients who developed DILI ( = 16). We did not confirm our hypothesis; however, we found that the combination of present genotype, null genotype, fast acetylators, and c1/c1 genotype had a significant risk for the development of ADR (OR 11; = 0.017; 95% CI: (0.54-186.35)). We propose that the presence of the present genotype, null genotype, fast acetylators, and c1/c1 genotype in the Peruvian population could be considered a risk factor for the development of ADR due to therapeutic drug intake.