Charactering the metabolism of cryptotanshinone by human P450 enzymes and uridine diphosphate glucuronosyltransferases in vitro

• 来源期刊: 中国药理学报（英文版）
• 关键词: cryptotanshinone P450 enzymes uridine diphosphate glucuronosyltransferases metabolic characteristics human liver microsomes
• 年，卷（期）: 2018,（8）
• 页码范围: 1393-1404
• 页数: 12页
• 语种: 英文
• DOI: 10.1038/aps.2017.144

摘要

Cryptotanshinone (CT) is the main active component in the root of Salvia miltiorrhiza Bunge (SMB) that displays antibacterial,anti-inflammatory and anticancer activities.In this study,we characterized phase Ⅰ and phase Ⅱ metabolism of GT in human liver microsomes in vitro and identified the metabolic enzymes (GYPs and UGTs) involved.The metabolites of CT generated by GYPs were detected using LC-MS/MS and the GYP subtypes involved in the metabolic reactions were identified using chemical inhibitors of GYP enzymes and recombinant human GYP enzymes (CYP1A2,CYP2A6,CYP2C8,CYP2C9,CYP2C19,CYP2D6,and CYP3A4).Glucuronidation of CT was also examined,and the UGT subtypes involved in the metabolic reactions were identified using recombinant human UGT enzymes (1A1,1A3,1A4,1A5,1A6,1A7,1A8,1A9,1A10,2B4,2B7,2B15 and 2B17).After adding NADPH to the human liver microsomes incubation system,CT was transformed into 6 main dehydrogenation and hydroxylation metabolites.CYP2A6,CYP3A4 and CYP2C19 were the major contributors to the transformation of its hydroxylation metabolites.CYP2C19,CYP1A2 and CYP3A4 were the major contributors to the transformation of its hydrogenation metabolites in human liver microsomes.This study showed that the metabolites at mn/z of 473 were mediated by UGT1A9 and that the metabolites at m/z of 489 were mediated by UGT2B7 and UGT2B4.CT was extensively metabolized by UGTs following metabolism by GYPs in the liver.