Enzymes and Pathways of Kavain Bioactivation and Biotransformation.
Enzymes and Pathways of Kavain Bioactivation and Biotransformation.
复制标题
卡瓦因生物活化和生物转化的酶和途径。
DOI：
10.1021/acs.chemrestox.9b00098
复制
发表时间：
2019
影响因子：
4.1
通讯作者：
Ma,Xiaochao
中科院分区：
文献类型：
--
作者：
Wang,Pengcheng;Zhu,Junjie;Shehu,AminaI;Lu,Jie;Chen,Jing;Zhong,Xiao-Bo;Ma,Xiaochao
Kavain 是Piper methysticum Forst 中的活性和主要成分。 （卡瓦），是一种广泛使用的膳食补充剂，用于治疗焦虑、失眠和压力。然而，含有卡瓦的产品会引起肝毒性，其潜在机制尚未得到充分研究。细胞色素 P450 (CYP) 介导的生物活化和生物转化与药物毒性高度相关。在当前的研究中，我们分析了卡瓦因在小鼠肝脏、尿液和粪便中的代谢途径。总体而言，鉴定出 28 种卡瓦因代谢物，其中包括 17 种新代谢物。卡瓦因的代谢途径包括谷胱甘肽（GSH）结合、氧化、脱氢、O-去甲基化、硫酸化和葡萄糖醛酸化。卡瓦因-谷胱甘肽加合物的鉴定表明卡瓦因在肝脏中形成了反应性代谢物。我们进一步说明，CYP2C19是一种高度多态性和诱导性的酶，是促进卡瓦因生物转化和生物活化的主要酶。我们的数据可用于通过防止潜在的草药-药物相互作用和肝毒性来指导卡瓦产品的安全使用。
Kavain is an active and major component inPiper methysticum Forst. (kava), which is a widely used dietary supplement for the treatment of anxiety, insomnia, and stress. However, kava-containing products can cause liver toxicity, and its underlying mechanisms are understudied. Cytochrome P450s (CYPs)-mediated bioactivation and biotransformation are highly associated with drug toxicity. In the current study, we profiled the metabolic pathways of kavain in mouse liver, urine, and feces. Overall, 28 kavain metabolites were identified including 17 new ones. The metabolic pathways of kavain include glutathione (GSH) conjugation, oxidation, dehydrogenation, O-demethylation, sulfation, and glucuronidation. The identification of kavain–GSH adducts suggests the formation of reactive metabolites of kavain in the liver. We further illustrated that CYP2C19, a highly polymorphic and inducible enzyme, was the major enzyme contributing to kavain biotransformation and bioactivation. Our data can be used to guide the safe use of kava products by preventing potential herb–drug interactions and hepatotoxicity.