Department of Pharmacology, JIPMER, Puducherry, India.
Department of Pathology, JIPMER, Puducherry, India.
J Pharm Pharmacol. 2021 Mar 8;73(4):473-486. doi: 10.1093/jpp/rgaa048.
Anti-TB drugs-isoniazid and rifampicin induced hepatotoxicity present a significant clinical problem. We aimed to evaluate the beneficial effect of gallic acid in anti-TB drug-induced liver injury in vivo and for the mechanism of action, we explored the influence of gallic acid on Nrf2 and NF-κB pathways.
We assessed serum liver function tests and histopathological analysis for the preventive effect of gallic acid on liver injury. For exploring the beneficial mechanism, we studied Nrf2 and NF-κB signalling pathways using molecular assays. Subsequently, we conducted in vitro cytotoxicity assays with Nrf2(ML385) and NF-κB(BAY 11-7085) antagonists.
Gallic acid co-administration attenuated the elevation of liver function enzymes, hepatic necrosis and inflammation compared to the anti-TB drug treatment alone. Mechanistic investigations reveal that gallic acid increased Nrf2 activation and induction of its downstream targets, preventing cytotoxicity by isoniazid and rifampicin. The protective effect of gallic acid diminished in the presence of Nrf2 antagonists in vitro. Furthermore, we found that gallic acid treatment inhibited NF-κB/TLR-4 axis upregulated by the anti-TB drugs.
Gallic acid is effective in preventing isoniazid and rifampicin induced hepatotoxicity in vivo by improving the redox homeostasis by activating Nrf2 and inhibiting NF-κB signalling pathways.
抗结核药物异烟肼和利福平诱导的肝毒性是一个重大的临床问题。我们旨在评估没食子酸在体内抗结核药物诱导的肝损伤中的有益作用，并探讨其对 Nrf2 和 NF-κB 通路的影响。
我们评估了血清肝功能试验和组织病理学分析，以评估没食子酸对肝损伤的预防作用。为了探索有益的机制，我们使用分子测定法研究了 Nrf2 和 NF-κB 信号通路。随后，我们用 Nrf2（ML385）和 NF-κB（BAY 11-7085）拮抗剂进行了体外细胞毒性测定。
与单独使用抗结核药物相比，没食子酸联合治疗可降低肝酶、肝坏死和炎症的升高。机制研究表明，没食子酸增加了 Nrf2 的激活和其下游靶标的诱导，从而防止了异烟肼和利福平的细胞毒性。体外 Nrf2 拮抗剂的存在减弱了没食子酸的保护作用。此外，我们发现没食子酸处理抑制了抗结核药物上调的 NF-κB/TLR-4 轴。
没食子酸通过激活 Nrf2 和抑制 NF-κB 信号通路来改善氧化还原稳态，从而有效预防体内异烟肼和利福平引起的肝毒性。
