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

Zhang-He Goh,Han Kiat Ho,Jie Kai Tee

doi:10.3390/ijms21103714

Zhang-He Goh, Han Kiat Ho + Show 1 more

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https://doi.org/10.3390/ijms21103714

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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, that is, pyrazinamide (PZA) and isoniazid (INH), are associated with such hepatotoxicity. Yet, we lack 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. 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.

Highlights

Tuberculosis is an infectious lung disease caused by Mycobacterium tuberculosis, with one in four people affected globally [1]
The drug-induced liver injury (DILI) arising from anti-tubercular therapy (ATT) is a pressing problem that needs to be addressed in tuberculosis
While silibinin has been reported to exhibit an indirect antioxidative effect by upregulating the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)–antioxidant response element (ARE) pathway [65], we found that silibinin’s hepatoprotection in LO2 was independent of glutamate-cysteine ligase catalytic subunit (Gclc), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), and sulfiredoxin 1 (Srxn1) induction (Figure 5A)

Summary

Introduction

Tuberculosis is an infectious lung disease caused by Mycobacterium tuberculosis, with one in four people affected globally [1]. Rat studies have been conducted on PZA, INH, and RMP, as well as various combinations of these drugs. Administration of these combinations has led to increased membrane lipid peroxidation levels [10], increased serum levels of liver enzymes [11,12], and reduced antioxidant protein levels [12,13]. The search for strategies to reduce PZA- and INH-induced hepatotoxicity is further underscored by the first-line status of the HRZE regimen in ATT with few safer and efficacious alternatives [14,15]

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