Co-suppression by nicardipine, a calcium antagonist, of induction of microsomal lauric acid hydroxylation with peroxisome proliferation in clofibrate-treated rat liver.
The in vivo effect of nicardipine, a well-known calcium antagonist, on microsomal omega-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 100 mg/kg body weight. Similarly, the induction of peroxisomal beta-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. Contrarily, nicardipine induced the reductase activity and increased the hepatic content of cytochromes P-450 and b5. These results provide the first demonstration of a calcium antagonist, e.g. nicardipine acting as inhibitor of the induction of microsomal omega-oxidation, in association with the inhibition of peroxisome proliferation in animals. The suppression of drug-induced peroxisome proliferation and microsomal omega-oxidation by the calcium antagonist may help in elucidating the causal relationship of the induction mechanisms between peroxisomal and microsomal enzymes.
Department of Clinical Biochemistry, Tokyo College of Pharmacy, Japan.
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T
Watanabe
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H
Itoga
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S
Okawa
H
H
Tamura
T
T
Suga
D000818:Animals; D002994:Clofibrate / Q000494:pharmacology*; D006900:Hydroxylation; D066298:In Vitro Techniques; D007850:Lauric Acids / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008830:Microbodies / Q000187:drug effects*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009529:Nicardipine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D007850:Lauric Acids; C030358:lauric acid; D009529:Nicardipine; D002994:Clofibrate