Econazole and miconazole inhibit steroidogenesis and disrupt steroidogenic acute regulatory (StAR) protein expression post-transcriptionally

Abstract

The imidazole antifungal drugs econazole and miconazole have previously been shown to disrupt steroidogenesis in Leydig and adrenal cells by inhibiting 17α-hydroxylase/17,20-lyase (P450c17) enzyme activity, thus reducing the conversion of progesterone to androstenedione. However, a recent study in Y-1 adrenal cells indicated that these compounds may also reduce the availability of cholesterol to the cytochrome P450 side chain cleavage (P450 scc) enzyme, the first enzyme in the steroidogenic pathway. Since the steroidogenic acute regulatory protein (StAR) mediates the transfer of cholesterol from the outer to the inner mitochondrial membrane where the P450 scc enzyme resides, an action which constitutes the rate-limiting and acutely-regulated step in steroidogenesis, we hypothesized that these drugs may also reduce StAR expression and/or activity. Our studies demonstrate that these drugs reversibly inhibited (Bu) 2cAMP-stimulated progesterone production in a dose- and time-dependent manner in MA-10 cells without affecting total protein synthesis or P450 scc and 3β-hydroxysteroid dehydrogenase (3β-HSD) enzyme expression or activity. In contrast, they dramatically decreased (Bu) 2cAMP-stimulated StAR protein expression post-transcriptionally. This study indicates that StAR protein is susceptible to inhibition by at least some imidazole compounds that inhibit steroidogenesis.