Association of NAT2 promoter hypermethylation with susceptibility to hepatotoxicity due to antituberculosis drugs and biomarker potential

This study aimed to determine whether promoter methylation of N-acetyltransferase 2 (NAT2), a metabolic enzyme responsible for drug metabolism and detoxification, was correlated with clinical parameters indicating anti-tuberculosis drug-induced liver injury (ATDILI) in tuberculosis patients and might emerge as an ATDILI biomarker. NAT2 promoter methylation in blood leukocyte of 102 tuberculosis patients (49 ATDILI cases and 53 non-ATDILI cases) and 100 healthy controls were quantified using quantitative real-time methylation-specific polymerase chain reaction. Compared to healthy volunteers, tuberculosis patients had significantly reduced NAT2 demethylation index. Compared with non-ATDILI patients, NAT2 demethylation index was significantly decreased in ATDILI patients. An independent association was found between lower NAT2 demethylation index and increased susceptibility to ATDILI. NAT2 demethylation index quantified after starting treatment within 1-7 days was negatively correlated with serum aminotransferases measured within 8-60 days of treatment. ROC curve analysis uncovered that NAT2 demethylation index was found to be a more sensitive and specific biomarker for ATDILI when compared to serum aminotransferases measured following treatment initiation within 1-7 days. Kaplan-Meier analysis unveiled a notable association between lower NAT2 demethylation index and a higher incidence of ATDILI in tuberculosis patients, as confirmed by Cox regression analysis while accounting for confounding variables. A reduction in NAT2 demethylation index could reflect ATDILI progression and potentially be used as a new, specific biomarker for ATDILI.