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 GSTT1 and GSTM1 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 GSTM1 and GSTT1, respectively. We found that the prevalence of the GSTM1 genotype was 52.79% and 47.21% for presence and null, respectively, and for GSTT1 it was 69.76% and 30.24% for presence and null, respectively. Neither genotype was prevalent in the patients who developed DILI (n = 16). We did not confirm our hypothesis; however, we found that the combination of GSTM1 present genotype, GSTT1 null genotype, fast NAT2 acetylators, and CYP2E1 c1/c1 genotype had a significant risk for the development of ADR (OR 11; p = 0.017; 95% CI: (0.54–186.35)). We propose that the presence of the GSTM1 present genotype, GSTT1 null genotype, fast NAT2 acetylators, and CYP2E1 c1/c1 genotype in the Peruvian population could be considered a risk factor for the development of ADR due to therapeutic drug intake.

The Peruvian Genome Project: expanding the global pool of genome diversity from South America

“…This allowed us to evaluate the effects of migration over thousands of years as well as helping differentiate populations based on evolutionary bottlenecks, revealing a distinct genetic fingerprint on the Americans' ancestors 22 . Moreover, we have found that the degree of ancestry (mestizos vs natives) and the geographic altitude habitat (high vs low landers) are linked 23 .…”

“…Our initial results point to greater hepatotoxicity in antiretroviral cotreatment on the coast. Thus, by considering the genetic diversity within and between populations, healthcare providers are beginning to better predict adverse drug reactions, adjust dosages, and select the most appropriate medication, thereby enhancing patient safety and treatment efficacy 30,31 .…”

Traditional Medicinal Plants with Significant Protection Against Antitubercular Drug-induced Liver Injury: A Systematic Review

“…These first-line medications are documented to induce mild to severe liver injury leading to the discontinuance of treatment that give rise to drug resistance and a cure not being achieved. 7 For instance, RIF causes thrombocytopenia, pain, nausea, and hepatitis in combination with other drugs; PZA leads to oxidative stress, arthralgia, and hepatitis through the 5-hydroxypyrazinoic acid; neuritis and color blindness are linked to ethambutol toxicity; while ethionamide leads to diarrhea and hepatotoxicity. 8, 9 Collectively, these ATDs elicit toxic metabolites, free radicals and reactive oxygen species (ROS) to become the main cause of injury to the liver.…”

Las OMICAS y la tuberculosis en el Perú: su impacto en el curso, diagnóstico y tratamiento

“…Esto implicaría que la isoniacida sería una de las drogas hepatotóxicas y su concentración debería disminuirse en aquellos pacientes que presenten el polimorfismo de acetilador lento; de otro lado, la dosis de rifampicina debería incrementarse para disminuir el riesgo de monoresistencia (6) . La asociación entre el genotipo y el desarrollo de hepatotoxicidad ha sido reportado (7) . Después de la infección por M. tuberculosis no todos desarrollamos la enfermedad y una de las causas estaría relacionada con el cromosoma 3q23 (8) .…”