Department of Pharmacology, JIPMER, Puducherry, India.
Department of Pathology, JIPMER, Puducherry, India.
Can J Physiol Pharmacol. 2021 Sep;99(9):952-963. doi: 10.1139/cjpp-2021-0008. Epub 2021 Feb 22.
Isoniazid and rifampicin are crucial for treating tuberculosis (TB); however, they can cause severe hepatotoxicity leading to liver failure. Therapeutic options are limited and ineffective. We hypothesized that prophylaxis with quercetin attenuates isoniazid- and rifampicin-induced liver injury. We randomly divided Wistar rats into seven groups ( = 6). The animals received isoniazid and rifampicin or were co-treated with quercetin or silymarin for 28 days. The protective effect of quercetin was assessed using liver function tests and liver histology. Nuclear factor erythroid 2-related factor 2 (NRF2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways were explored to elucidate the mechanism of action. Quercetin co-administration prevented the elevation of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and bilirubin compared with isoniazid and rifampicin treatment alone. In the histological analysis, we observed that quercetin prophylaxis lessened the severity of hepatic necrosis and inflammation compared with the anti-TB drug-treated group. Quercetin attenuated anti-TB drug-induced oxidative stress by increasing NRF2 activation and expression, boosting endogenous antioxidant levels. Additionally, quercetin blocked inflammatory mediators high mobility group box-1 (HMGB-1) and interferon γ (IFN-γ), inhibiting activation of the NF-κB/ toll like receptor 4 (TLR-4) axis. Quercetin protects against anti-TB liver injury by activating NRF2 and blocking NF-κB/TLR-4.
异烟肼和利福平是治疗结核病（TB）的关键药物；然而，它们可能导致严重的肝毒性，导致肝衰竭。治疗选择有限且无效。我们假设槲皮素预防可以减轻异烟肼和利福平引起的肝损伤。我们将 Wistar 大鼠随机分为七组（每组 n = 6）。动物接受异烟肼和利福平或同时用槲皮素或水飞蓟素治疗 28 天。使用肝功能试验和肝组织学评估槲皮素的保护作用。探索核因子红细胞 2 相关因子 2（NRF2）和核因子κ轻链增强子的激活 B 细胞（NF-κB）途径，以阐明作用机制。与单独使用异烟肼和利福平治疗相比，槲皮素联合用药可防止丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、碱性磷酸酶（ALP）和胆红素升高。在组织学分析中，我们观察到与抗结核药物治疗组相比，槲皮素预防减轻了肝坏死和炎症的严重程度。槲皮素通过增加 NRF2 的激活和表达，提高内源性抗氧化剂水平，减轻抗结核药物引起的氧化应激。此外，槲皮素阻断了炎症介质高迁移率族蛋白 1（HMGB-1）和干扰素 γ（IFN-γ），抑制了 NF-κB/ toll 样受体 4（TLR-4）轴的激活。槲皮素通过激活 NRF2 和阻断 NF-κB/TLR-4 来保护抗结核药物引起的肝损伤。
