Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P.R. China.
State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou 550025, P.R. China.
Chem Res Toxicol. 2021 Jun 21;34(6):1612-1618. doi: 10.1021/acs.chemrestox.1c00060. Epub 2021 Apr 19.
Labetalol hydrochloride (LHCl), an α- and β-adrenoreceptor blocker, is widely used for the treatment of hypertension as well as angina pectoris. Previous reports have demonstrated the adverse events during clinical application of LHCl, such as liver injury and acute renal failure. The present study aimed to investigate metabolic activation of LHCl to initiate the elucidation of the mechanisms of its liver toxicity. One glutathione (GSH) conjugate was detected in rat and human primary hepatocytes as well as bile of rats after exposure to LHCl. The GSH conjugate was chemically synthesized and characterized by Q-TOF and H NMR. Pretreatment of 2,6-dichloro-4-nitrophenol (DCNP), a broad-spectrum sulfotransferase (SULT) inhibitor, significantly attenuated the formation of the GSH conjugate in LHCl-treated hepatocytes and animals, indicating the participation of SULTs in metabolic activation of LHCl. Moreover, pretreatment with DCNP displayed significant protection against the observed cytotoxicity in rat primary hepatocytes, which suggests a correlation of the bioactivation of LHCl mediated by SULTs with LHCl-induced hepatotoxicity.
盐酸拉贝洛尔（LHCl）是一种α-和β-肾上腺素能受体阻滞剂，广泛用于治疗高血压和心绞痛。先前的报告表明，LHCl 在临床应用中会出现不良反应，如肝损伤和急性肾衰竭。本研究旨在探讨 LHCl 的代谢激活，以阐明其肝毒性的机制。在暴露于 LHCl 后，在大鼠和人原代肝细胞以及大鼠胆汁中检测到一种谷胱甘肽（GSH）缀合物。通过 Q-TOF 和 H NMR 对 GSH 缀合物进行了化学合成和表征。用 2,6-二氯-4-硝基苯酚（DCNP）预处理，一种广谱磺基转移酶（SULT）抑制剂，可显著减少 LHCl 处理的肝细胞和动物中 GSH 缀合物的形成，表明 SULT 参与了 LHCl 的代谢激活。此外，用 DCNP 预处理对大鼠原代肝细胞中观察到的细胞毒性具有显著的保护作用，这表明 SULT 介导的 LHCl 的生物活化与 LHCl 诱导的肝毒性相关。
