Zhang Jinhui, Li Li, Tang Suni, Hale Thomas W, Xing Chengguo, Jiang Cheng, Lü Junxuan
Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
Clinical Research Unit, School of Medicine, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
Am J Chin Med. 2015;43(6):1211-30. doi: 10.1142/S0192415X1550069X. Epub 2015 Sep 22.
We have shown that the in vitro hepatic microsomal metabolism of pyranocoumarin compound decursinol angelate (DA) to decursinol (DOH) exclusively requires cytochrome P450 (CYP) enzymes, whereas the conversion of its isomer decursin (D) to DOH can be mediated by CYP and esterase(s). To provide insight into specific isoforms involved, here we show with recombinant human CYP that 2C19 was the most active at metabolizing D and DA in vitro followed by 3A4. With carboxylesterases (CES), D was hydrolyzed by CES2 but not CES1, and DA was resistant to both CES1 and CES2. In human liver microsomal (HLM) preparation, the general CYP inhibitor 1-aminobenzotriazole (ABT) and respective competitive inhibitors for 2C19 and 3A4, (+)-N-3-benzylnirvanol (NBN) and ketoconazole substantially retarded the metabolism of DA and, to a lesser extent, of D. In healthy human subjects from a single-dose pharmacokinetic (PK) study, 2C19 extensive metabolizer genotype (2C1917 allele) tended to have less plasma DA AUC0-48h and poor metabolizer genotype (2C192 allele) tended to have greater DA AUC0-48h. In mice given a single dose of D/DA, pretreatment with ABT boosted the plasma and prostate levels of D and DA by more than an order of magnitude. Taken together, our findings suggest that CYP isoforms 2C19 and 3A4 may play a crucial role in the first pass liver metabolism of DA and, to a lesser extent, that of D in humans. Pharmacogenetics with respect to CYP genotypes and interactions among CYP inhibitor drugs and D/DA should therefore be considered in designing future translation studies of DA and/or D.
我们已经表明，吡喃香豆素化合物当归酰紫花前胡醇（DA）在体外肝微粒体中代谢为紫花前胡醇（DOH）完全需要细胞色素P450（CYP）酶，而其异构体紫花前胡素（D）转化为DOH可由CYP和酯酶介导。为深入了解所涉及的特定同工型，我们在此用重组人CYP表明，2C19在体外代谢D和DA时活性最高，其次是3A4。对于羧酸酯酶（CES），D可被CES2水解，但不能被CES1水解，而DA对CES1和CES2均有抗性。在人肝微粒体制剂中，一般的CYP抑制剂1-氨基苯并三唑（ABT）以及2C19和3A4的各自竞争性抑制剂（+）-N-3-苄基尼凡诺（NBN）和酮康唑，在很大程度上抑制了DA的代谢，对D的代谢抑制作用较小。在单剂量药代动力学（PK）研究的健康人类受试者中，2C19广泛代谢者基因型（2C1917等位基因）的血浆DA AUC0-48h往往较低，而代谢不良者基因型（2C192等位基因）的血浆DA AUC0-48h往往较高。在单次给予D/DA的小鼠中，用ABT预处理可使D和DA的血浆及前列腺水平提高一个多数量级。综上所述，我们的研究结果表明，CYP同工型2C19和3A4可能在人类DA的首过肝代谢中起关键作用，对D的首过肝代谢作用较小。因此，在设计未来DA和/或D的转化研究时，应考虑CYP基因型的药物遗传学以及CYP抑制剂药物与D/DA之间的相互作用。
