The interaction of representative members from two classes of antimycotics--the azoles and the allylamines--with cytochromes P-450 in steroidogenic tissues and liver.
Spectrophotometric studies with ketoconazole, clotrimazole and miconazole show strong type-II interactions with several cytochromes P-450, particularly (Ks greater than 10(7)M-1; pH7.4; 25 degrees C) with the 11 beta-hydroxylase of adrenal mitochondria, with the 17 alpha/20 lyase of testis microsomes and with some forms of cytochromes P-450 of liver. A tight binding of the azoles also occurs to the reduced cytochromes, giving rise to an impeded CO binding to the haem iron. The binding of the azoles to 11 beta-hydroxylase and 17 alpha/20 lyase is much tighter than the binding of endogenous substrates, and consequently inhibition of steroidogenesis will occur at these sites. The metabolism of xenobiotic substrates by the cytochromes P-450 of liver will also be severely impeded. In contrast, the allylamines naftifine and SF 86-327 are type-I substrates for a small portion of cytochromes P-450 of liver microsomes only and there is no spectral evidence for binding to the cytochromes P-450 involved in steroid biosynthesis.
D000311:Adrenal Glands / Q000378:metabolism; D000499:Allylamine / Q000031:analogs & derivatives / Q000378:metabolism*; D000588:Amines / Q000378:metabolism*; D000818:Animals; D000935:Antifungal Agents / Q000378:metabolism*; D001393:Azoles / Q000378:metabolism*; D002417:Cattle; D003022:Clotrimazole / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008825:Miconazole / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D013053:Spectrophotometry; D000077291:Terbinafine; D013737:Testis / Q000378:metabolism
D000588:Amines; D000935:Antifungal Agents; D001393:Azoles; D009281:Naphthalenes; D000499:Allylamine; C029178:naftifine; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; D003022:Clotrimazole; D000077291:Terbinafine; D007654:Ketoconazole