Some Aspects of the Control of Dehydroepiandrosterone Synthesis in the Human Adrenal Gland in Vitro

SUMMARY The control of dehydroepiandrosterone (DHA) synthesis in the human adrenal gland was studied by investigating the biosynthesis of its immediate precursor, 17-hydroxypregnenolone (3β,17α-dihydroxy-pregn-5-en-20-one) and the side-chain cleavage. Both conversions take place in the microsomal fraction and there is an obligatory requirement for the co-factor, reduced nicotinamide adenine dinucleotide phosphate (NADPH). Under optimal conditions, 17-hydroxylation is controlled only by the availability of the substrate and the co-factor. By using the same kinetic approach it was observed that the synthesis of DHA is controlled by the availability of substrate and co-factor. However, the reaction was inhibited by the oxidized form (NADP+) and when the ratio of NADP+:NADPH reached 1, the maximum velocity was halved. Two major metabolites of 17-hydroxypregnenolone, namely DHA and 17-hydroxyprogesterone, are non-competitive inhibitors of the reaction. The inhibition constants are of the magnitude of the tissue concentration of these steroids in the adrenal gland which suggests that non-competitive inhibition takes place in vivo.