Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy , University of Pittsburgh , Pittsburgh , Pennsylvania 15261 , United States.
Department of Pharmaceutical Sciences, School of Pharmacy , University of Connecticut , Storrs , Connecticut 06269 , United States.
Chem Res Toxicol. 2019 Jul 15;32(7):1335-1342. doi: 10.1021/acs.chemrestox.9b00098. Epub 2019 Jul 2.
Kavain is an active and major component in . (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.
卡瓦胡椒素是卡瓦（一种常用于治疗焦虑、失眠和压力的膳食补充剂）的一种活性和主要成分。然而，含卡瓦的产品可能会导致肝毒性，其潜在机制还在研究中。细胞色素 P450 （CYP）介导的生物激活和生物转化与药物毒性高度相关。在本研究中，我们对卡瓦胡椒素在小鼠肝、尿和粪便中的代谢途径进行了分析。总共鉴定出 28 种卡瓦胡椒素代谢物，包括 17 种新代谢物。卡瓦胡椒素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。卡瓦胡椒素-GSH 加合物的鉴定表明卡瓦胡椒素在肝脏中形成了反应性代谢物。我们进一步表明，CYP2C19 是一种高度多态性和诱导性的酶，是导致卡瓦胡椒素生物转化和生物激活的主要酶。我们的数据可用于通过预防潜在的草药-药物相互作用和肝毒性来指导卡瓦产品的安全使用。
