Abstract

1. Venlafaxine (VLF), an antidepressant agent, is widely used to combat major depressive disorders, particularly for the treatment of selective serotonin reuptake inhibitor-resistant depression. VLF has been shown to cause liver injury. The present study aimed to investigate the metabolic activation of VLF and explore the mechanisms of hepatotoxicity induced by VLF.

2. One glutathione (GSH) conjugate and one cysteine conjugate were both detected in mouse and human liver microsomal incubations containing VLF and GSH or cysteine. The two conjugates were also detected in cultured mouse primary hepatocytes and bile of rats after exposure to VLF. The in vitro and in vivo studies demonstrated that VLF was metabolized to a quinone methide intermediate reactive to GSH and cysteine residues of hepatic protein. The observed protein covalent binding revealed dose-dependency. The metabolic activation of VLF was P450-dependent, and CYP3A4 was found as the predominant enzyme involved in the bioactivation process.

3. These findings facilitate better understanding of the metabolic activation-hepatotoxicity relationship of VLF and provide chemists with information about new potential structural alerts during drug design process.

摘要

1. 文拉法辛 (VLF) 是一种抗抑郁药，广泛用于对抗重度抑郁症，特别是用于治疗选择性 5-羟色胺再摄取抑制剂耐药的抑郁症。VLF 已被证明会导致肝损伤。本研究旨在研究 VLF 的代谢活化并探讨 VLF 诱导的肝毒性机制。

2. 在含有 VLF 和 GSH 或半胱氨酸的小鼠和人类肝脏微粒体孵育中均检测到一种谷胱甘肽 (GSH) 偶联物​​和一种半胱氨酸偶联物。在暴露于 VLF 后，在培养的小鼠原代肝细胞和大鼠胆汁中也检测到这两种结合物。在体外和体内研究表明，VLF被代谢为醌甲基化物中间体的反应性，以GSH和肝蛋白质的半胱氨酸残基。观察到的蛋白质共价结合揭示了剂量依赖性。VLF 的代谢激活依赖于 P450，并且发现 CYP3A4 是参与生物激活过程的主要酶。

3. 这些发现有助于更好地了解 VLF 的代谢激活-肝毒性关系，并为化学家提供有关药物设计过程中新的潜在结构警报的信息。