School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, People's Republic of China.
School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, People's Republic of China.
Drug Des Devel Ther. 2020 Oct 22;14:4423-4438. doi: 10.2147/DDDT.S274627. eCollection 2020.
Berberrubine (BRB), an isoquinoline alkaloid, is a major constituent of medicinal plants Franch or Schneid. BRB exhibits various pharmacological activities, whereas exposure to BRB may cause toxicity in experimental animals.
In this study, we thoroughly investigated the liver injury induced by BRB in mice and rats. To explore the underlying mechanism, a study of the metabolic activation of BRB was conducted. Furthermore, covalent modifications of cysteine residues of proteins were observed in liver homogenate samples of animals after exposure to BRB, by application of an exhaustive proteolytic digestion method.
It was demonstrated that BRB-induced hepatotoxicities in a time- and dose-dependent manner, based on the biochemical parameters ALT and AST. H&E stained histopathological examination showed the occurrence of obvious edema in liver of mice after intraperitoneal (i.p.) administration of BRB at a single dose of 100 mg/kg. Slight hepatotoxicity was also observed in rats given the same doses of BRB after six weeks of gavage. As a result, four GSH adducts derived from reactive metabolites of BRB were detected in microsomal incubations with BRB fortified with GSH as a trapping agent. Moreover, four cys-based adducts derived from reaction of electrophilic metabolites of BBR with proteins were found in livers.
These results suggested that the formation of protein adducts originating from metabolic activation of BRB could be a crucial factor of the mechanism of BRB-induced toxicities.
小檗红碱（BRB）是一种异喹啉生物碱，是药用植物 Franch 或 Schneid 的主要成分。BRB 具有多种药理活性，而暴露于 BRB 可能会导致实验动物中毒。
在这项研究中，我们深入研究了 BRB 在小鼠和大鼠中引起的肝损伤。为了探讨其潜在机制，我们对 BRB 的代谢激活进行了研究。此外，通过应用彻底的蛋白水解消化方法，观察到暴露于 BRB 后动物肝匀浆样品中蛋白质半胱氨酸残基的共价修饰。
基于 ALT 和 AST 等生化参数，证明 BRB 以时间和剂量依赖的方式诱导肝毒性。H&E 染色的组织病理学检查显示，腹腔内（i.p.）给予 BRB 100mg/kg 单剂量后，小鼠肝脏出现明显水肿。同样剂量的 BRB 灌胃 6 周后，大鼠也出现轻微肝毒性。结果，在 BRB 加 GSH 作为捕获剂的微粒体孵育中检测到来自 BRB 反应性代谢物的四个 GSH 加合物。此外，在肝脏中发现了源自 BBR 亲电代谢物与蛋白质反应的四个基于半胱氨酸的加合物。
这些结果表明，BRB 代谢激活形成的蛋白质加合物可能是 BRB 诱导毒性机制的关键因素。
