An Evaluation of the In Vitro Roles and Mechanisms of Silibinin in Reducing Pyrazinamide- and Isoniazid-Induced Hepatocellular Damage

Abstract

Tuberculosis remains a significant infectious lung disease that affects millions of patients worldwide. Despite numerous existing drug regimens for tuberculosis, Drug-Induced Liver Injury is a major challenge that limits the effectiveness of these therapeutics. Two drugs that form the backbone of the commonly administered quadruple antitubercular regimen, i.e. pyrazinamide (PZA) and isoniazid (INH), are associated with such hepatotoxicity. The problem is compounded by the lack of safe and effective alternatives to the antitubercular regimen. Consequently, current research largely focuses on exploiting the hepatoprotective effect of nutraceutical compounds as complementary therapy. Silibinin, a herbal product widely believed to protect against various liver diseases, potentially provides a useful solution given its hepatoprotective mechanisms. In our study, we identified silibinin's role in mitigating PZA-and INH-induced hepatotoxicity and elucidated a deeper mechanistic understanding of silibinin's hepatoprotective ability. 25 μ M silibinin preserved the viability of human foetal hepatocyte line LO2 when co-administered with 80 mM INH and decreased apoptosis induced by a combination of 40 mM INH and 10 mM PZA by reducing oxidative damage to mitochondria, proteins, and lipids. Taken together, this proof-of-concept forms the rational basis for the further investigation of silibinin's hepatoprotective effect in subsequent preclinical studies and clinical trials.

Hepatoprotective activity of melittin on isoniazid- and rifampicin-induced liver injuries in male albino rats

“…It could also be suggested that the administration of MEL may prevent liver damage related to the maintenance of plasma membrane integrity, thereby suppressing the leakage of enzymes through membranes. Additionally, MEL may also exhibit hepatocurative activity against the hepatotoxicity induced by a combination of INH and RIF drugs [ 35 ]. Mel15 and Mel30 treatment reduced the elevation of AST and ALT activities; with MEL groups showing greater improvement than the NR group.…”