Inhibition of steroid-mediated induction of delta-aminolevulinic acid synthase by 2-diethylaminoethyl-2,2-diphenylvalerate HCl (SKF 525-A).

The inhibition of the steroid-mediated induction of delta-aminolevulinate synthase, the rate-limiting enzyme in hepatic porphyrin-heme biosynthesis, by 2-diethylaminoethyl-2,2-diphenylvalerate HCl (SKF 525-A) as studied in cultured chick embryo liver cells. The formation of porphyrins in response to cyproterone, a synthetic steroid, was inhibited in a time-dependent manner by SKF 525-A, an inhibitor of several drug metabolizing enzyme systems. This action is a result of an inhibitory effect of SKF 525-A on the cyproterone-mediated induction of delta-aminolevulinate synthase; SKF 525-A also inhibited the induction of the enzyme by the naturally occurring 5 beta-H steroids, etiocholanolone and pregnanolone. Employing [3H]etiocholanolone, we provide evidence that this inhibition is not associated with either decreased uptake or an altered metabolism of the steroid. Moreover, approx 4-6-fold more radioactivity was associated with [3H]etiocholanolone-treated cells cultured in the presence of SKF 525-A. Alternative mechanisms for the induction of delta-aminolevulinate synthase by steroids are proposed which do not require the interaction of steroid-receptor complex with the genome.