Unraveling the Role of CYP2E1 in Antitubercular Drug-Induced Hepatotoxicity: From Molecular Mechanisms to Clinical Implications.

Abstract

Antitubercular (AT) drugs, particularly isoniazid (INH), rifampicin (RIF), pyrazinamide (PYZ), and ethambutol (EMB), are the cornerstone of tuberculosis (TB) treatment. However, their use is often limited by the risk of hepatotoxicity, a potentially severe side effect. Among the factors implicated in drug-induced liver injury, cytochrome P450 2E1 (CYP2E1) is emerging as a key enzyme in the pathogenesis of hepatotoxicity. CYP2E1 is involved in the oxidative metabolism of many xenobiotics, including AT drugs, and is known to produce reactive oxygen species (ROS) during the metabolism process, which can lead to cellular damage. This review investigates the potential role of CYP2E1 in the mechanisms behind AT drug-induced hepatotoxicity and explores the biochemical and molecular pathways through which CYP2E1 might contribute to liver injury. Genetic polymorphisms in the CYP2E1 gene, which affect its activity, may also play a role in individual susceptibility to AT drug-induced hepatotoxicity. This review also deals with how multifactorial interactions including genetic polymorphisms in CYP2E1, N-acetyl transferase 2 (NAT2), and glutathione-S-transferase (GST), as well as factors such as drug-drug interactions, nutritional status, coexisting infections (e.g., hepatitis B/C), and alcohol consumption collectively modulate individual susceptibility to AT drug-induced hepatotoxicity. By elucidating the role of CYP2E1 in AT drug-induced hepatotoxicity, this review provides a foundation for future therapeutic strategies, including the development of safer drug formulations or adjunct therapies targeting CYP2E1 to mitigate hepatotoxicity.