Isoniazid (INH) and rifampicin (RIF) are cornerstone first-line antituberculosis drugs, yet their clinical utility is often limited by drug-induced liver injury (DILI). Understanding the mechanistic basis of INH and RIF-induced hepatotoxicity is essential for developing effective preventive and therapeutic strategies. This review provides a comprehensive overview of hepatic metabolism and bioactivation pathways of INH and RIF, highlighting how their co-administration potentiates synergistic hepatotoxic effects. We further explore genetic polymorphisms in drug-metabolizing enzymes and epigenetic modifications, including DNA methylation and histone remodeling, which modulate susceptibility to hepatotoxicity. Special attention is given to the epigenetic regulation of key detoxification enzymes such as cytochrome P450 2E1 (CYP2E1), N-acetyltransferase 2 (NAT2), glutathione S-transferase Mu 1 (GSTM1), glutathione S-transferase (GST) theta 1 (GSTT1), UDP glucuronosyltransferase family 1 member A1 (UGT1A1), and nuclear factor-erythroid 2-related factor 2 (NRF2) pathway. Additionally, we examined immune-mediated mechanisms, including hapten formation, Tool-like receptor-4 (TLR4) driven innate immune responses, and human leukocyte antigen (HLA) associated adaptive recognition, which integrated with toxic insults under the dual-hit hypothesis. By elucidating the interplay between metabolism, genetics, epigenetics, and immune pathways, this review highlights emerging insights into the pathogenesis of INH and RIF-induced hepatotoxicity, offering potential avenues for precision risk assessment and hepatoprotective interventions.
Batool et al. (Sun,) studied this question.