Effect of ketoconazole, etomidate and other inhibitors of steroidogenesis on cytochrome P-450sccII-catalyzed reactions

Abstract

The effects of a variety of certain inhibitors of adrenal steroidogenesis have been studied on the reconstituted C21-steroid 17 alpha-hydroxylase-17,20-lyase system, whose protein components, the enzyme 17 alpha-hydroxylase-17,20-lyase(P-450sccII) and its reductase, are extensively purified from pig testis microsomes. We found: (1) Ketoconazole (cis-1-acetyl-4-[4-((2-(2,4-dichlorophenyl)-2-(1H-imidazole-1- ylmethyl-1,3-dioxalan-4-ol)methoxy)phenyl] piperazine and Etomidate(R-(+)-ethyl-[1-(a-methyl-benzyl)-indol-5-carboxylatel), inhibited cleavage of 17 alpha-hydroxy progesterone at the 17,20-bond to give androstenedione in a dose-dependent fashion. (2) Some other inhibitors of steroidogenesis, Metyrapone (2-methyl-1.2di-3-pyridyl-1-propanone), Trilostane (4,5-epoxy-17-hydroxy-3-oxo androstane-2-carbonitrile),o,p'DDD (1-(O-chlorophenyl)-1-(p-chlorophenyl)2,2-dichloroethane) and Aminoglutethimide (p-(alpha-aminopheny)-alpha-ethylglutaramide) did not inhibit the same 17,20-lyase system. (3) All of the above listed inhibitors, over a wide variety of concentration ranges, had no significant effect on the 17 alpha-hydroxylation of 11 beta-hydroxyprogesterone, which had been shown to be catalyzed by the same P-450sccII. (4) NADPH:P-450 reductase was not inhibited by all of the above listed inhibitors.