title: Comparative effects of the azole-based fungicide flusilazole on yeast and mammalian lanosterol 14 alpha-methyl demethylase.
abstract: Flusilazole inhibits the 14 alpha-demethylation of [24,25-3H-2]dihydrolanosterol by yeast and rat liver cell-free preparations. The 50% inhibitory concentration of demethylation shows that the yeast system is 100 times more sensitive than the rat system. Purified rat liver P-45014DM is about 10 times more sensitive to flusilazole than crude rat liver microsomes. Binding constants in microsomes indicate that yeast preparations (Kd, 21 nM) bind flusilazole with a higher affinity than rat liver (Kd, 496 nM). Purified rat liver P-45014DM (Kd, 45 nM) binds flusilazole with an affinity similar to that of the yeast enzyme. The P-450-dependent cholesterol 7 alpha-hydroxylase in rat liver microsomes is more sensitive to flusilazole than P-45014DM. The results indicate that selectivity of azole antimycotics is not due to inherent sensitivity differences between fungal and mammalian 14 alpha-demethylase; rather, in crude enzyme systems, a protective effect is afforded by other susceptible isozymes present in mammalian systems.
authors.affiliation: Experimental Station, E.I. du Pont de Nemours and Company, Incorporated, Wilmington, Delaware 19898.
authors.forename: J M
authors.initials: JM
authors.lastname: Trzaskos
authors.forename: M J
authors.initials: MJ
authors.lastname: Henry
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D012821:Silanes / Q000494:pharmacology*; D012825:Silicon / Q000494:pharmacology*; D058886:Sterol 14-Demethylase; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; C548417:Cyp51 protein, rat; D012821:Silanes; D014230:Triazoles; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; D002790:Cholesterol 7-alpha-Hydroxylase; C061365:flusilazole; D012825:Silicon