The effects of o,p'-DDD on adrenal steroidogenesis and hepatic steroid metabolism

O,p'-DDD is used for the treatment of adrenocortical carcinoma and Cushing's disease. The inhibitory effect of this drug on the adrenal steroid biosynthesis has been described by many authors, but there are very few reports about the sites of action of this drug on adrenal steroid synthesis. This paper presents in vitro studies on adrenal steroidogenesis and hepatic steroid metabolism. The effects of o,p'-DDD on adrenal 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 11 beta-hydroxylase (11 beta-OHlase) and 18-hydroxylase (18-OHlase) were examined in vitro using mitochondrial and microsomal fractions prepared by standard centrifugation procedures from the homogenate of bovine adrenal cortices. The concentrations of o,p'-DDD inducing 50% inhibition of 3 beta-HSD, 11 beta-OHlase and 18-OHlase were 8 X 10(-6) M, 1 X 10(-5) M and 3 X 10(-6) M, respectively. This study clearly demonstrates the marked inhibitory effects of o,p'-DDD on 3 beta-HSD in vitro, which was not described previously. The inhibitory effects of o,p'-DDD on these 3 enzymes were diminished by an addition of 0.05 approximately 0.5 mM of cofactor (NADPH or NAD). The results indicate that o,p'-DDD may reduce NADPH or NAD utilization, resulting in the inhibition of steroidogenesis. The effects of o,p'-DDD on hepatic 5 beta-reductase were examined in vitro using rat liver homogenate. O,p'-DDD inhibits 5 beta-reductase, resulting in the decrease of conversion of cortisol to dihydrocortisol and tetrahydrocortisol at the concentration of 10(-3) M.