RT Journal Article
SR Electronic
T1 Coinduction of multiple hepatic cytochrome P-450 proteins and their mRNAs in rats treated with imidazole antimycotic agents.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 279
OP 285
VO 35
IS 3
A1 K A Hostetler
A1 S A Wrighton
A1 D T Molowa
A1 P E Thomas
A1 W Levin
A1 P S Guzelian
YR 1989
UL http://molpharm.aspetjournals.org/content/35/3/279.abstract
AB 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.