Cyproterone-Mediated Stimulation of δ-Aminolevulinic Acid Synthetase in Chick Embryo Liver Cells

Abstract

In cultured chick embryo liver cells, cyproterone and cyproterone acetate, synthetic antiandrogenic steroids, were potent inducers of mitochondrial .delta.-aminolevulinic acid (ALA) synthetase, the rate-limiting enzyme in the heme biosynthetic pathway. Both steroids increased enzyme activity at 5 .mu.M and produced a maximal stimulation, 36-fold for cyproterone and 29-fold for cyproterone acetate, at 55 .mu.M. The dose-response curves of the steroids differed, however, in that cyproterone acetate produced a greater mean stimulation of the enzyme at concentrations less than approximately 25 .mu.M; at higher concentrations, cyproterone was the more effective inducer. Increased activity of ALA synthetase was not apparent until about 12 h after the addition of cyproterone, and maximal activity was not achieved until 20-24 h. The induction of ALA synthetase by these antiandrogens was prevented by actinomycin D, cordycepin, anisomycin, cycloheximide and puromycin. New RNA and protein synthesis are probably necessary for enzyme induction. The cyproterone-mediated induction of the enzyme was inhibited 50% by 2 .mu.M heme, the putative physiological inhibitor of ALA synthetase. These antiandrogens, unlike other potent steroid inducers of this enzyme in chick embryo liver, do not possess either a 5.beta.-pregnane or 5.beta.-androstane nucleus. The stimulation of hepatic ALA synthetase represents the 1st example of a direct effect of these steroids on enzyme induction.