THE IMPACT OF AMBIENT STEROID CONCENTRATIONS UPON THE RELATIVE ACTIVITIES ADRENAL MICROSOMAL 3β-HYDROXYSTEROID DEHYDROGENASE AND 17, 20-DESMOLASE

Abstract

We found that intra-adrenal concentrations of most steroids are 2-10 times higher in adults than in infants, and reach levels (10−7-10−5 M) which might influence steroidogenic efficiency. Since 3β-HSD and 17,20-desmolase act on 17OH-pregnenolone to determine relative DHA and cortisol production during human development, we studied their kinetics in adrenal microsomes from 6 kidney donors (12-40 yr) and the effect of varying steroid concentrations on their activities. There was no age-related change in Km for 3β-HSD (0.1-0.5 μM) or desmolase (0.2-1.7 μM). At all ages Vmax for 3β-HSD (3-8 nmol/mg/min) exceeded that for desmolase (0.3-1.4 nmol/mg/min). Physiological intra-adrenal concentrations (10−6 M) of progesterone, 170H-prog., 11-desoxycortisol, corticosterone, androstenedione and testosterone caused >20% inhibition of 3β-HSD, with no effect on desmolase. Estradiol and estrone caused >95% inhibition of 3β-HSD with only minimal impact on desmolase. Kinetic analysis showed competitive and non-competitive inhibition with Ki values of 10−7-10−5 M. These data demonstrate that ambient steroids can render 3β-HSD rate-limiting and permit desmolase to compete for 170H-pregnenolone substrate. This phenomenon provides a rational explanation both for the relative 3β-HSD deficiency of the human fetus and the increased C-19 steroid production during adrenarche.