Abstract
ASDI inhibitors stoichiometrically bind to enzyme active-sties have a high degree of “lock and key” specificity, cannot be removed from the active site by dilution and should have few side effects. Two synthetic steroids selected as ASDI candidates, 17β-ureidoandrosta-I, 4-dien-3-one and 16β-bromo-5α-pregnan-3β, 17α-diol-11, 20-dione were found to inhibit the conversion of pregnenolone or progesterone to testosterone by adult rat testicular microsomes specifically at the level of both 17α hydroxylase and C17-20 lyase. When administered to pregnant rats at 30mg/kg daily from day 13 to day 21 each inhibitor significantly blocked penis formation in male offspring by reducing anogenital distance from 3.69 ± 0.24mm. (control) to 3.26 ± 0.22 (17β-ureide) and 3.32 ± 0.23mm. (16β-bromide). Testosterone production in vitro by experimental tests was only 25% of that of controls with either pregnenolone or progesterone as substrates. Abnormal accumulations of progesterone and 17-hydroxyprogesterone were present in incubations of experimental tests. Female fetuses and maternal and fetal adrenal size and steroid synthesis were unaffected. Each inhibitor obliterated C19 steroid excretion in urines and feces of adult female rats as analyzed by gas-liquid chromatography and mass spectrometry. Thus, these inhibitors appear to block sex hormone without affecting glucorcorticoid synthesis in adult and fetal rats.
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Goldman, A. Inhibition of masculine differentiation in male rat fetuses by two candidates for active-site-directed-irreversible (ASDI) inhibitors of 17α hydroxylase and C17–20 Lyase. Pediatr Res 5, 400 (1971). https://doi.org/10.1203/00006450-197108000-00120
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DOI: https://doi.org/10.1203/00006450-197108000-00120