title: A comparative study of 1-substituted imidazole and 1,2,4-triazole antifungal compounds as inhibitors of testosterone hydroxylations catalysed by mouse hepatic microsomal cytochromes P-450.
abstract: Three imidazole antifungal agents, ketoconazole, miconazole and tioconazole, and a group of structurally related 1-substituted imidazole and 1,2,4-triazole compounds were evaluated as inhibitors of the oxidative metabolism of testosterone catalysed by mouse hepatic microsomal cytochromes P-450. Spectroscopic studies showed that both imidazoles and triazoles interacted with ferric cytochrome P-450 in hepatic microsomes to produce type II difference spectra which could be distinguished by their different absorbance maxima; 429-430 nm and 425-426 nm respectively. Compound 4, which possesses both types of functional group, produced a spectrum which resembled that of imidazole compounds, indicating that the imidazole moiety had a higher affinity than the triazole for the haem of cytochromes P-450 present in microsomes. The test compounds differentially inhibited regio- and stereo-specific testosterone metabolism and the pattern of inhibition varied with the 1-substituent on the azole ring. Ketoconazole was a potent inhibitor of testosterone 6 beta-hydroxylation (IC50 0.08 microM) but was considerably less active against other hydroxylations and 17 beta-oxidation to androstenedione (IC50 range 13 to greater than 100 microM). In contrast, tioconazole (IC50 range 0.18 to 3.3 microM) and miconazole (IC50 range 0.15 to 10 microM) were relatively non-selective. Compounds 1 and 2, which differed from each other only in the type of azole ring, were most active against 16 beta-hydroxylation. The triazole analogue (compound 2) was a significantly more potent inhibitor of 16 beta-hydroxylation than the imidazole (compound 1), equipotent against androstenedione formation and less active against the other hydroxylations. Two relatively polar bis-azole analogues (compounds 3 and 4) were most active against androstenedione formation; however, in general they were less inhibitory than the lipophilic azoles. We conclude that azole antifungal agents of differing structure show different patterns of selective interaction with cytochromes P-450, a phenomenon primarily dependent on the 1-substituent on the azole ring, but also modulated to a lesser extent by the type of azole ring (imidazole or triazole).
authors.affiliation: Biological Laboratory, The University, Canterbury, Kent, U.K.
authors.forename: S A
authors.initials: SA
authors.lastname: Ballard
authors.forename: A
authors.initials: A
authors.lastname: Lodola
authors.forename: M H
authors.initials: MH
authors.lastname: Tarbit
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D002855:Chromatography, Thin Layer; D065607:Cytochrome P-450 Enzyme Inhibitors; D006900:Hydroxylation; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D013057:Spectrum Analysis; D013250:Steroid Hydroxylases / Q000378:metabolism; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D014230:Triazoles; D013739:Testosterone; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C022724:testosterone 7-alpha-hydroxylase, hamster