Mäenpää J, Juvonen R, Raunio H, Rautio A, Pelkonen O
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Biochem Pharmacol. 1994 Oct 7;48(7):1363-9. doi: 10.1016/0006-2952(94)90558-4.
Methoxsalen (8-methoxypsoralen) is a very potent inhibitor of human cytochrome P450 2A6 (CYP2A6) and mouse Cyp2a-5-mediated coumarin 7-hydroxylation in vitro. To determine the effect of methoxsalen on coumarin 7-hydroxylation in humans in vivo, five subjects were given 45 mg of methoxsalen and 5 mg of coumarin. Methoxsalen inhibited in vivo coumarin metabolism by 47 +/- 9.2% (mean +/- SEM). Methoxsalen was metabolized in human liver microsomes at the rate of 50-100 pmol/mg protein/min (approx. 30% of the activity in mouse liver microsomes). Metabolism was not inhibited by the anti-Cyp2a-5 antibody in human liver microsomes. NIH 3T3 cells stably expressing catalytically active CYP2A6 enzyme did not metabolize methoxsalen, indicating that CYP2A6 does not accept methoxsalen as a substrate. In pyrazole-induced mouse liver microsomes, methoxsalen metabolism was inhibited by the anti-Cyp2a-5 antibody. Cyp2a-5 protein expressed in the yeast Saccharomyces cerevisiae was capable of metabolizing methoxsalen, indicating that methoxsalen is a substrate of Cyp2a-5. Although kinetic studies indicated that the inhibition of coumarin 7-hydroxylation by methoxsalen is competitive in human liver microsomes, methoxsalen does not appear to be a substrate for CYP2A6. Methoxsalen and coumarin have the potential of strong metabolic interactions in man.
甲氧沙林（8-甲氧基补骨脂素）在体外是一种非常有效的人类细胞色素P450 2A6（CYP2A6）和小鼠Cyp2a - 5介导的香豆素7-羟化作用的抑制剂。为了确定甲氧沙林在人体内对香豆素7-羟化作用的影响，对5名受试者给予了45毫克甲氧沙林和5毫克香豆素。甲氧沙林在体内抑制香豆素代谢47±9.2%（平均值±标准误）。甲氧沙林在人肝微粒体中的代谢速率为50 - 100皮摩尔/毫克蛋白质/分钟（约为小鼠肝微粒体中活性的30%）。人肝微粒体中的代谢不受抗Cyp2a - 5抗体的抑制。稳定表达具有催化活性的CYP2A6酶的NIH 3T3细胞不能代谢甲氧沙林，这表明CYP2A6不将甲氧沙林作为底物。在吡唑诱导的小鼠肝微粒体中，甲氧沙林的代谢受到抗Cyp2a - 5抗体的抑制。在酿酒酵母中表达的Cyp2a - 5蛋白能够代谢甲氧沙林，这表明甲氧沙林是Cyp2a - 5的底物。尽管动力学研究表明在人肝微粒体中甲氧沙林对香豆素7-羟化作用的抑制是竞争性的，但甲氧沙林似乎不是CYP2A6的底物。甲氧沙林和香豆素在人体内有产生强烈代谢相互作用的可能性。
