Cytochrome P-450 as a target of azole antifungal agents

Abstract

Azole antifungal agents inhibit fungal P-450_14DM which catalyzes the 14α-demethylation of lanosterol. Judging from their affinity for the reconstituted lanosterol demethylase system of yeast, azole antifungal agents are classified into two categories. The first one contains potent inhibitors that can quantitatively bind to P-450_14DM and inhibit the demethylase below 0.1 μM. The second one includes weaker inhibitors that require more than 1 μM for complete inhibition of the demethylase. Antifungal agents classified as the first category interfere with binding of CO to ferrous P-450_14DM.
Azole antifungal agents inhibit the lanosterol 14 α-demethylation by rat liver microsomes. These compounds also inhibit other mammalian cytochrome P-450 s such as steroid hormone synthesizing and drug metabolizing enzymes. Affinity of antifungal agents for rat liver demethylase is lower than that for the yeast enzyme especially for the first group compounds. This fact indicates that azole antifungal agents classified as the first category show some selectivity for fungal P-450_14DM. For systemically applicable antifungal agents, selectivity for the fungal enzyme is required for their safety. Accordingly, more extensive studies on interaction between azole antifungal agents and various cytochrome P-450 s are expected.