Coinduction of multiple hepatic cytochrome P-450 proteins and their mRNAs in rats treated with imidazole antimycotic agents.
To characterize the molecular basis by which imidazole antimycotic drugs increase cytochrome P-450, we examined the effects of treating female rats with clotrimazole, miconazole, or ketoconazole on expression of the major inducible forms of hepatic cytochromes P-450 (P-450p, P-450b/e, P-450c/d, and P-450j). From measurements of the content of immunoreactive cytochromes P-450 in liver microsomes and of the amounts of liver RNA hybridizing to cloned P-450 cDNAs, we established that the glucocorticoid-responsive P-450p is the form predominantly induced by clotrimazole, miconazole, and ketoconazole, to as much as 382 times above control values. The phenobarbital-responsive cytochromes P-450b/e were also induced strongly by clotrimazole and miconazole, but not by ketoconazole. Aromatic hydrocarbon-inducible cytochromes P-450c/d were modestly elevated by each of these three antifungal drugs whereas ethanol-responsive P-450j was marginally induced by ketoconazole, but not by clotrimazole or miconazole. In some, but not all cases, treatment of rats with antifungal drugs resulted in accumulation of P-450 protein that significantly exceeded the increase in the corresponding P-450 mRNA. In conclusion, imidazole antifungal drugs differentially modulate the expression of at least four distinct gene subfamilies of rat hepatic cytochrome P-450 by separate mechanisms involving accumulation of P-450 mRNA and protein.
Hostetler
K A
KA
Life Science Research, Hershey Foods Corporation, Hershey, Pennsylvania 17033.
Wrighton
S A
SA
Molowa
D T
DT
Thomas
P E
PE
Levin
W
W
Guzelian
P S
PS
D000818:Animals; D003022:Clotrimazole / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis; D007654:Ketoconazole / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology*; D008825:Miconazole / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D014217:Troleandomycin / Q000494:pharmacology
D007093:Imidazoles; D007527:Isoenzymes; D012333:RNA, Messenger; D008825:Miconazole; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D003022:Clotrimazole; D007654:Ketoconazole