CYP2E1, GSTM1, and GSTT1 genetic polymorphisms and their associations with susceptibility to antituberculosis drug-induced liver injury in Thai tuberculosis patients

Wanvisa Udomsinprasert,Supharat Suvichapanich,Usa Chaikledkaew,Jiraphun Jittikoon,Surakameth Mahasirimongkol,Sukanya Wattanapokayakit,Taisei Mushiroda,Nusara Satproedprai,Noppadol Chanhom

doi:10.1016/j.heliyon.2021.e06852

Abstract

Antituberculosis drug-induced liver injury (ATDILI) is the common adverse reaction of antituberculosis drugs. Glutathione S-transferases (GSTs), which are phase II metabolizing enzymes for detoxification, are recognized as potential mediators of hepatotoxicity. However, role of GSTs polymorphisms in ATDILI pathogenesis has never been observed in Thais. This study aimed to investigate associations between GSTs and ATDILI susceptibility. This retrospective case-control multicentered study was conducted by the collaboration from ten secondary and tertiary care hospitals across Thailand, including Northern, Central, and Southern parts of Thailand. We enrolled 80 tuberculosis (TB) patients with ATDILI and 174 those without ATDILI into the study. Polymerase chain reaction (PCR) was used to determine genetic polymorphisms of GSTM1 and GSTT1 genes. CYP2E1 genotyping data were derived from microarray data. We illustrated that GSTT1 null and GSTM1/GSTT1 dual null genotypes were correlated with an increased risk of ATDILI with odds ratio (OR) at 1.83 (95% confidence interval (CI), 1.00 to 3.35; P = 0.049) and 2.12 (95%CI, 1.02 to 4.38; P = 0.044), respectively. Interestingly, GSTT1 null and GSTM1/GSTT1 dual null genotypes were found to be correlated with an increased risk of ATDILI in Thai TB patients who carried CYP2E1 wild type phenotype with OR 2.99 (95%CI, 1.07 to 8.39; P = 0.037) and 3.44 (95%CI, 1.01 to 11.71; P = 0.048), respectively. Collectively, GSTT1 null and GSTM1/GSTT1 dual null genotypes were associated with a higher risk of ATDILI in Thai TB patients, which may serve as alternative genetic biomarkers for ATDILI.

Highlights

Hepatotoxicity is the most frequent cause of tuberculosis (TB) treatment discontinuation that increases the incident rate of multi-drugresistant TB and leads to treatment failure [1]
We found that GSTT1 null and GSTM1/GSTT1 dual null genotypes were both correlated with an increased risk of Antituberculosis drug-induced liver injury (ATDILI) in Thai TB patients
In our subgroup analyses based on CYP2E1 polymorphisms, we found that GSTT1 homozygous null genotype and GSTM1/GSTT1 dual null genotype were both associated with the risk of ATDILI in CYP2E1 wild type allele group

Summary

Introduction

Hepatotoxicity is the most frequent cause of tuberculosis (TB) treatment discontinuation that increases the incident rate of multi-drugresistant TB and leads to treatment failure [1]. The majority of TB patients with drug-induced liver injury (DILI) develop irreversible liver failure and eventually require liver transplant, due to a poorly defined pathogenesis and delayed diagnosis [2]. NAT2 phenotypes can be categorized into four groups including rapid, intermediate, slow, and ultra-slow acetylators [6]. Slow acetylation of INH can result in the increased concentrations of hydrazine and acetylhydrazine, INH toxic metabolites, which increased the toxicity of the drug and subsequently induced the progressive and developmental ATDILI in TB patients [2]. Some TB patients who carried NAT2 rapid and intermediate acetylation phenotypes had a possibility of developing ATDILI. Other genes must be taken into account in order to increase ATDILI predictability using a genetic biomarker

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