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In vitro and in vivo metabolic activation of rhein and characterization of glutathione conjugates derived from rhein
Chemico-Biological Interactions ( IF 5.1 ) Pub Date : 2018-01-11
Yang Xu, Xu Mao, Boyang Qin, Ying Peng, Jiang Zheng

Rhein (RH), 4,5-dihydroxyanthrauinone-2-carboxylic acid, is found in rhubarb (Dahuang), a traditional herbal medicine. RH has reportedly demonstrated multiple pharmacologic properties. Previous studies have also shown that RH induced hepatotoxicity, but the mechanisms of the adverse effect remain unknown. The major objective of the present study was to study the metabolic pathways of RH in order to identify potential reactive metabolites. One mono-hydroxylation metabolite (M1) was detected in urine and bile of rats given RH. M1 was also observed in rat and human liver microsomal incubations after exposure to RH. A total of three (GSH) conjugates (M2, M3 and M5) were detected in bile of rats treated with RH. We concluded that M2-M3 were directly derived from parent compound RH through spontaneous reaction with GSH. M5 was derived from M1 by reaction with GSH, which required cytoslic GSTs. M5 was further metabolized to the corresponding NAC conjugate (mercapturic acid) and was excreted in urine. P450 2C9 was mainly involved in the oxidation of RH.



中文翻译:

大黄酸的体外体内代谢活化以及大黄酸衍生的谷胱甘肽偶联物的表征

大黄(一种传统的草药)中发现有大黄酸(4,5-二羟基蒽醌-2-羧酸)大黄酸(RH)。据报道,RH已显示出多种药理特性。先前的研究还表明,RH可诱发肝毒性,但不良反应的机制仍不清楚。本研究的主要目的是研究RH的代谢途径,以确定潜在的反应性代谢产物。在给予RH的大鼠的尿液和胆汁中检测到一种单羟基化代谢物(M1)。在暴露于RH后的大鼠和人肝脏微粒体培养物中也观察到了M1。在用RH处理的大鼠的胆汁中总共检测到三种(GSH)缀合物(M2,M3和M5)。我们得出的结论是,M2-M3通过与GSH的自发反应直接衍生自母体化合物RH。M5是通过与GSH反应从M1衍生而来的,GSH需要胞质GST。M5进一步代谢为相应的NAC共轭物(巯基酸),并从尿中排出。P450 2C9主要参与RH的氧化。

更新日期:2018-01-11
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