Otton S V, Tyndale R F, Wu D, Inaba T, Kalow W, Sellers E M
Addiction Research Foundation, Toronto, Ontario, Canada.
Drug Metab Dispos. 1992 Jan-Feb;20(1):1-5.
In vivo pharmacogenetic studies have suggested that the monkey may be an animal model for the human polymorphism of cytochrome P-450 2D6 (also called cytochrome P-450db1). In the present study, the catalytic, immunologic, and electrophoretic properties of cytochrome P-450db1 in liver microsomes from African green monkeys (Cercopithecus aethiops) were examined and compared with P-450db1 in human liver microsomes. Using sparteine as the substrate, the activity of microsomal P-450db1 from the two sources was indistinguishable in terms of the pattern of sparteine metabolites produced, the apparent Ki values of 8 competitive inhibitors (r = 0.94, p less than 0.001), and the extent of immunoinhibition by anti-rat P-450db1 antibody. Kinetic analyses demonstrated that the apparent KM values of the high affinity component of sparteine oxidation in monkey liver microsomes fell within the range observed in human livers; the Vmax of this component was as much as six times greater than the highest value reported for human liver. Western immunoblots showed a protein band in monkey liver microsomes that co-migrated with P-450db1 in human liver. The high degree of similarity observed here between P-450db1 of monkey and human liver microsomes suggests that the monkey will be a good animal model for P-450db1 enzyme studies, and possibly for studies of the role of this enzyme in drug abuse and dependence.
体内药物遗传学研究表明，猴子可能是细胞色素P - 450 2D6（也称为细胞色素P - 450db1）人类多态性的动物模型。在本研究中，检测了非洲绿猴（猕猴属埃塞俄比亚种）肝微粒体中细胞色素P - 450db1的催化、免疫和电泳特性，并与人类肝微粒体中的P - 450db1进行了比较。以司巴丁为底物，从产生的司巴丁代谢物模式、8种竞争性抑制剂的表观Ki值（r = 0.94，p小于0.001）以及抗大鼠P - 450db1抗体的免疫抑制程度来看，两种来源的微粒体P - 450db1活性没有差异。动力学分析表明，猴肝微粒体中司巴丁氧化高亲和力成分的表观KM值落在人类肝脏中观察到的范围内；该成分的Vmax比人类肝脏报道的最高值高多达六倍。蛋白质免疫印迹显示猴肝微粒体中有一条蛋白带与人类肝脏中的P - 450db1共迁移。猴和人类肝微粒体的P - 450db1之间观察到的高度相似性表明，猴子将是P - 450db1酶研究的良好动物模型，也可能是该酶在药物滥用和成瘾中作用研究的良好动物模型。
