The interaction of representative members from two classes of antimycotics—the azoles and the allylamines—with cytochromes P-450 in steroidogenic tissues and liver

Abstract

1. Spectrophotometric studies with ketoconazole, clotrimazole and miconazole show strong type-II interactions with several cytochromes P-450, particularly (K_s10⁷M⁻¹; pH 7.4; 25.C) with the 11β-hydroxylase of adrenal mitochondria, with the 17α/20 lyase of testis microsomes and with some forms of cytochromes P-450 of liver.

2. A tight binding of the azoles also occurs to the reduced cytochromes, giving rise to an impeded CO binding to the haem iron.

3. The binding of the azoles to 11β-hydroxylase and 17α/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.

4. 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.