Comparative induction of cytochrome P4504A in rat hepatocyte culture by the peroxisome proliferators, bifonazole and clofibrate.
1. The influence of imidazole and triazole antifungal drugs on cytochrome P450 levels in male Wistar primary rat hepatocyte culture for 70 h has been investigated and compared with clofibrate. 2. Bifonazole, clotrimazole, geniconazole clofibrate induced total P450 in hepatocytes, whereas itraconazole, miconazole and UK-47,265 did not. 3. When the CYP4A subfamily was examined, only bifonazole and clofibrate induced CYP4A as assessed by both Western blot analysis and the 11- and 12-hydroxylation of lauric acid. 4. By analysis of concentration-response curves in hepatocyte culture, bifonazole was 160 and 40 times more potent than clofibrate for induction of the 11- and 12-hydroxylation of lauric acid respectively. 5. Taken collectively, our data have identified bifonazole as a relatively potent, non-carboxylate inducer of CYP4A and the mechanism of induction and specificity of this azole is discussed.
Sabzevari
O
O
Molecular Toxicology Group, School of Biological Sciences, University of Surrey, Guildford, UK.
Hatcher
M
M
O'Sullivan
M
M
Kentish
P
P
Gibson
G
G
D000818:Animals; D002478:Cells, Cultured; D002994:Clofibrate / Q000494:pharmacology*; D003022:Clotrimazole / Q000494:pharmacology; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D007093:Imidazoles / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008825:Miconazole / Q000494:pharmacology; D008830:Microbodies / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar
D007093:Imidazoles; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; D003022:Clotrimazole; D002994:Clofibrate; C036596:bifonazole