Guo Ying, Li Feng, Ma Xiaochao, Cheng Xingguo, Zhou Honghao, Klaassen Curtis D
Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University Changsha, Hunan, People's Republic of China.
Xenobiotica. 2011 Nov;41(11):996-1005. doi: 10.3109/00498254.2011.597456. Epub 2011 Jul 25.
Berberine is a widely used plant extract for gastrointestinal infections, and is reported to have potential benefits in treatment for diabetes and hypercholesterolemia. It has been suggested that interactions between berberine-containing products and cytochromes P450 (CYPs) exist, but little is known about which CYPs mediate the metabolism of berberine in vivo. In this study, berberine metabolites in urine and feces of mice were analyzed, and the role that CYPs play in producing these metabolites were characterized in liver microsomes from mice (MLM) and humans (HLM), as well as recombinant human CYPs. Eleven berberine metabolites were identified in mice, including 5 unconjugated metabolites, mainly in feces, and 6 glucuronide and sulfate conjugates, predominantly in urine. Three novel berberine metabolites were observed. Three unconjugated metabolites of berberine were produced by MLM, HLM, and recombinant human CYPs. CYP2D6 was the primary recombinant human CYP producing these metabolites, followed by CYP1A2, 3A4, 2E1 and CYP2C19. The metabolism of berberine in MLM and HLM was decreased the most by a CYP2D inhibitor, and moderately by inhibitors of CYP1A and 3A. CYP2D plays a major role in berberine biotransformation, therefore, CYP2D6 pharmacogenetics and potential drug-drug interactions should be considered when berberine is used.
黄连素是一种广泛用于治疗胃肠道感染的植物提取物，据报道在糖尿病和高胆固醇血症治疗中具有潜在益处。有人提出含黄连素产品与细胞色素P450（CYPs）之间存在相互作用，但对于体内哪些CYPs介导黄连素的代谢知之甚少。在本研究中，分析了小鼠尿液和粪便中的黄连素代谢物，并在小鼠肝微粒体（MLM）、人肝微粒体（HLM）以及重组人CYPs中表征了CYPs在产生这些代谢物中所起的作用。在小鼠中鉴定出11种黄连素代谢物，包括5种未结合代谢物，主要存在于粪便中，以及6种葡萄糖醛酸和硫酸盐结合物，主要存在于尿液中。观察到3种新的黄连素代谢物。MLM、HLM和重组人CYPs产生了3种黄连素的未结合代谢物。CYP2D6是产生这些代谢物的主要重组人CYP，其次是CYP1A2、3A4、2E1和CYP2C19。CYP2D抑制剂对MLM和HLM中黄连素代谢的抑制作用最强，CYP1A和3A抑制剂的抑制作用中等。CYP2D在黄连素生物转化中起主要作用，因此，使用黄连素时应考虑CYP2D6药物遗传学和潜在的药物相互作用。
