The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Biochem Pharmacol. 2018 Apr;150:9-23. doi: 10.1016/j.bcp.2018.01.026. Epub 2018 Jan 12.
Acetaminophen (APAP)-induced hepatotoxicity is the main cause of drug-induced liver injury. This study investigated the protection of baicalin and its aglycone baicalein against APAP-induced hepatotoxicity and its mechanism. Baicalein and baicalin alleviated APAP-induced hepatotoxicity both in vitro and in vivo. Moreover, this baicalin-provided protection was not diminished in hepatocytes or mice treated with β-glucuronidase inhibitor. Results of liver glutathione (GSH) and reactive oxygen species (ROS) formation demonstrated the alleviation of baicalein and baicalin on APAP-induced liver oxidative stress injury. Baicalein and baicalin induced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increased the expression of its downstream antioxidant genes. Baicalein and baicalin-provided protection was diminished after the application of Nrf2 siRNA in hepatocytes and Nrf2 knock-out mice. Molecular docking results indicate the potential interaction of baicalein and baicalin with kelch-like ECH-associated protein-1 (Keap1). Baicalein and baicalin induced the sustained phosphorylation of extracellular regulated protein kinases (ERK)1/2 and protein kinase C (PKC). Moreover, ERK1/2 and PKC inhibitors both abrogated Nrf2 phosphorylation and its subsequent activation, and the protection against APAP-induced hepatotoxicity induced by baicalein and baicalin. In summary, baicalein and baicalin alleviate APAP-induced hepatotoxicity by activating Nrf2 via blocking the binding of Nrf2 with Keap1 and inducing Nrf2 phosphorylation. ERK1/2 and PKC are both critical for regulating the phosphorylation of Nrf2 induced by baicalein or baicalin.
对乙酰氨基酚（APAP）诱导的肝毒性是药物性肝损伤的主要原因。本研究探讨了黄芩苷及其苷元黄芩素对 APAP 诱导的肝毒性的保护作用及其机制。黄芩素和黄芩苷在体外和体内均能减轻 APAP 诱导的肝毒性。此外，在经β-葡糖苷酸酶抑制剂处理的肝细胞或小鼠中，黄芩苷提供的保护作用并未减弱。肝谷胱甘肽（GSH）和活性氧（ROS）形成的结果表明，黄芩素和黄芩苷减轻了 APAP 诱导的肝氧化应激损伤。黄芩素和黄芩苷诱导核因子红细胞 2 相关因子 2（Nrf2）的激活，并增加其下游抗氧化基因的表达。在肝细胞和 Nrf2 敲除小鼠中应用 Nrf2 siRNA 后，黄芩素和黄芩苷提供的保护作用减弱。分子对接结果表明，黄芩素和黄芩苷与 Kelch 样 ECH 相关蛋白 1（Keap1）具有潜在的相互作用。黄芩素和黄芩苷诱导细胞外调节蛋白激酶（ERK）1/2 和蛋白激酶 C（PKC）的持续磷酸化。此外，ERK1/2 和 PKC 抑制剂均阻断了 Nrf2 的磷酸化及其随后的激活，以及黄芩素和黄芩苷对 APAP 诱导的肝毒性的保护作用。总之，黄芩素和黄芩苷通过阻断 Nrf2 与 Keap1 的结合并诱导 Nrf2 磷酸化，激活 Nrf2 来减轻 APAP 诱导的肝毒性。ERK1/2 和 PKC 对于调节黄芩素或黄芩苷诱导的 Nrf2 磷酸化均至关重要。
