Co-suppression by Nicardipine, a Calcium Antagonist, of Induction of Microsomal Lauric Acid Hydroxylation with Peroxisome Proliferation in Clofibrate-Treated Rat Liver

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The in vivo effect of nicardipine, a well-known calcium antagonist, on microsomal ω-oxidation of laurate in clofibrate-treated rat liver was studied. The 15.3-fold induction of the activity by 2 weeks administration of 0.25% clofibrate in the diet was markedly suppressed to about 6-fold by co-administration of nicardipine at 100mg/kg body weight. Similarly, the induction of peroxisomal β-oxidation and carnitine acetyltransferase activities were also suppressed by this simultaneous administration by more than 50%. Although clofibrate also induced the activity of reduced nicotineamide adenine dinucleotide phosphate (NADPH)-cytochrome c reductase and increased the hepatic content of cytochrome P-450,no suppressive effect of nicardipine was observed. Contarily, nicardipine induced the reductase activity and increased the hepatic content of cytochromes P-450 and b_5. These results provide the first demonstration of a calcium antagonist, e.g. nicardipine acting as inhibitor of the induction of microsomal ω-oxidation, in association with the inhibition of peroxisome proliferation in animals. The suppression of drug-induced peroxisome proliferation and microsomal ω-oxidation by the calcium antagonist may help in elucidating the causal relationship of the induction mechanisms between peroxisomal and microsomal enzymes.
社団法人日本薬学会の論文
1991-05-25