Yamazaki Hiroshi, Iketaki Hitomi, Shibata Ayaka, Nakajima Miki, Yokoi Tsuyoshi
Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
Drug Metab Pharmacokinet. 2002;17(1):47-53. doi: 10.2133/dmpk.17.47.
Juvenile visceral steatosis (jvs) mice, isolated from the C3H-H-2 degrees strain, exibit a systemic carnitine deficiency (SCD) phenotype and develop fatty liver, hyperammonemia and hypoglycemia. This phenotype is caused by a missense mutation (Leu352Arg) of a sodium-dependent carnitine/organic cation transporter, Octn2 (Slc22a5). The jvs mouse could be a useful model for pharmacokinetics and drug metabolism studies concerning Octn2 substrate drugs. In the present study, the effects of the SCD phenotype on the cytochrome P450 (P450 or CYP) dependent activities of four endobiotic and seven xenobiotic oxidations catalyzed by liver and kidney microsomes from jvs mice were investigated. The jvs-type mutation was genotyped by PCR-RFLP. The contents of total P450 and NADPH-P450 reductase were similar in the the liver microsomes from male or female mice of the wild-type and those heterozygous or homozygous for the jvs-type mutation. The 6beta-hydroxylation activities of testosterone and progesterone (marker for Cyp3a) based on the protein contents were 1.2- to 2.0-fold higher in liver microsomes from jvs/jvs-type mice compared to jvs/wt- or wt/wt-type mice. Coumarin 7-hydroxylation activities (marker for Cyp2a) were decreased to 0.7-fold in the male jvs/jvs-type mice. The activities of lauric acid 12-hydroxylation (a marker for Cyp4a) and aniline p-hydroxylation (a marker for Cyp2e1) in liver microsomes were increased 1.4- to 1.9-fold in female jvs/jvs-type mice. Genotoxic activation of 2-aminofluorene (a marker for Cyp4b1) by male and female mouse kidney microsomes were not affected by the SCD phenotype. These results demonstrated that the SCD phenotype affected the P450-dependent catalytic activities in liver microsomes. The jvs mouse could provide valuable information in drug interaction and drug metabolism studies of OCTN2 substrate drugs and new compounds in development.
从C3H-H-2°品系分离出的幼年内脏脂肪变性（jvs）小鼠表现出全身性肉碱缺乏（SCD）表型，并出现脂肪肝、高氨血症和低血糖。这种表型是由钠依赖性肉碱/有机阳离子转运体Octn2（Slc22a5）的错义突变（Leu352Arg）引起的。jvs小鼠可能是用于Octn2底物药物的药代动力学和药物代谢研究的有用模型。在本研究中，研究了SCD表型对jvs小鼠肝脏和肾脏微粒体催化的四种内源性和七种外源性氧化反应中细胞色素P450（P450或CYP）依赖性活性的影响。通过PCR-RFLP对jvs型突变进行基因分型。野生型以及jvs型突变杂合或纯合的雄性或雌性小鼠肝脏微粒体中总P450和NADPH-P450还原酶的含量相似。与jvs/wt型或wt/wt型小鼠相比，jvs/jvs型小鼠肝脏微粒体中基于蛋白质含量的睾酮和孕酮6β-羟化活性（Cyp3a的标志物）高1.2至2.0倍。香豆素7-羟化活性（Cyp2a的标志物）在雄性jvs/jvs型小鼠中降至0.7倍。雌性jvs/jvs型小鼠肝脏微粒体中月桂酸12-羟化活性（Cyp4a的标志物）和苯胺对羟化活性（Cyp2e1的标志物）增加了1.4至1.9倍。雄性和雌性小鼠肾脏微粒体对2-氨基芴（Cyp4b1的标志物）的遗传毒性激活不受SCD表型的影响。这些结果表明，SCD表型影响肝脏微粒体中P450依赖性催化活性。jvs小鼠可为OCTN2底物药物和正在开发的新化合物的药物相互作用和药物代谢研究提供有价值的信息。
