Hidestrand M, Oscarson M, Salonen J S, Nyman L, Pelkonen O, Turpeinen M, Ingelman-Sundberg M
Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
Drug Metab Dispos. 2001 Nov;29(11):1480-4.
In view of conflicting data in the literature regarding the enzyme(s) responsible for metabolism of selegiline, a drug used in the treatment of Parkinson's disease, investigations were carried out in vitro using the human cytochrome P450 enzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 recombinantly expressed in yeast to elucidate the enzyme specificity in selegiline metabolism. In the yeast microsomes used, desmethylselegiline and levomethamphetamine were formed from selegiline at significant rates. The highest contribution to the hepatic clearance of selegiline was calculated to be exerted by CYP2B6 (124 l/h) CYP2C19 (82 l/h), whereas CYP3A4 (27 l/h) and CYP1A2 (21 l/h) were of less importance. Antibodies against CYP2B6 inhibited metabolism of selegiline in microsomes containing CYP2B6 but not in microsomes without significant amounts of the enzyme. In contrast to previous reports, we could not find any role for CYP2D6 in the metabolism of selegiline. The data strongly indicate that the high extent of interindividual variation seen in vivo for selegiline clearance is caused by the metabolism of the compound by the highly polymorphic CYP2B6 and CYP2C19.
鉴于文献中关于司来吉兰（一种用于治疗帕金森病的药物）代谢相关酶的数据存在冲突，我们利用在酵母中重组表达的人细胞色素P450酶CYP1A1、CYP1A2、CYP2A6、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6、CYP2E1和CYP3A4进行了体外研究，以阐明司来吉兰代谢中的酶特异性。在所使用的酵母微粒体中，司来吉兰能以显著速率生成去甲基司来吉兰和左旋甲基苯丙胺。计算得出，对司来吉兰肝脏清除率贡献最大的是CYP2B6（124升/小时）和CYP2C19（82升/小时），而CYP3A4（27升/小时）和CYP1A2（21升/小时）的作用较小。针对CYP2B6的抗体抑制了含CYP2B6的微粒体中司来吉兰的代谢，但对不含大量该酶的微粒体则无此作用。与之前的报道不同，我们未发现CYP2D6在司来吉兰代谢中发挥任何作用。这些数据有力地表明，司来吉兰体内清除率个体间差异较大是由该化合物经高度多态性的CYP2B6和CYP2C19代谢所致。
