Activities of cytochrome P450 enzymes in liver and kidney microsomes from systemic carnitine deficiency mice with a gene mutation of carnitine/organic cation transporter

摘要

Juvenile visceralsteatosis (jvs) mice,isolated from the C3H-H-2deg 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 pharmaceokinetics and drug metabolism studies concerning Octn2 substrate drugs.In the present study,the effects of the SCD phenotype on the cytochromeP450 (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 liver microsomes from maleor female mice of the wild-type and those heterozygous or homozygous for the jvs-type mutation.The 6#beta#-hydroxylation activities of testosterone and progesterone (marker for Cyp3a) basedon the protein contents were 1.2 -to 2.0-fold higher in liver microsomes from jvs/jvs-type mice compared tojvs/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 Cyp4b10 by male and female mouse kidney microsomes were not affected by the SCD phenotype.These results demonstrated that the SCD phenotype affected theP450-dependent catalytic activities in liver microsomes.The jvs mouse could provide valuable information in drug interaction and drug metabolismstudies of OCTN2 substrae drugs and new compounds in development.