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

The imidazole antifungal drugs econazole and miconazole have previously bee n shown to disrupt steroidogenesis in Leydig and adrenal cells by inhibitin g 17 alpha -hydroxylase 17,20-lyase (P450c17) enzyme activity, thus reducin g the conversion of progesterone to androstenedione. However, a recent stud y in Y-1 adrenal cells indicated that these compounds may also reduce the a vailability of cholesterol to the cytochrome P150 side chain cleavage (P150 (sec)) enzyme the first enzyme in the steroidogenic pathway. Since the ster oidogenic acute regulatory protein (StAR) mediates the transfer of choleste rol from the outer to the inner mitochondrial membrane where the P450(sec) enzyme resides, an action which constitutes the rate-limiting and acutely-r egulated 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),cAMP-stimulated progesterone production in a dose- and time-dependent manner in MA-10 cells without affecting total p rotein synthesis or P350(sec) and 3 beta -hydroxysteroid dehydrogenase (3 b eta -HSD) enzyme expression or activity. In contrast, they dramatically dec reased (Bu)(2)cAMP-stimulated StAR protein expression post-transcriptionall y. This study indicates that StAR protein is: susceptible to inhibition by at least some imidazole compounds that inhibit steroidogenesis. (C) 2001 El sevier Science Ltd. All rights reserved.