Sex-Dependent Differences in Derangements of Biliary-Steroid-Excretion Patterns Produced by Cyanoketone in Rats.

Intramuscular injections of 25 mg/kg body weight of 2α-cyano-4,4,17α-trimethyl-5-androsten-17β-ol-3-one (cyanoketone) produces an immediate cessation of excretion of practically all corticosteroid metabolites (3α, 11β,15α-,21-tetrahydroxy-5α-pregnan-20-one and 3α- and 3β,11β, 21-trihydroxy-5α-pregnan-20-one) in bile from female rats. Instead, large amounts of 3β-hydroxy-5-pregnen-20-one, 3β,16α-dihydroxy-5-pregnen-20-one and 5-pregnene-3β,20α-diol are excreted. The total daffy excretion of steroids in bile from treated female animals is 2580 ± 580 μg compared to 850 μg in a female rat injected with solvent only. When ovariectomized rats are treated with cyanoketone, the principal biliary metabolites are 3β-hydroxy-5-pregnen-20-one and 3β,16α-dihydroxy-5-pregnen-20-one and the total daily excretion of steroids measured is 1186 ± 197 μg indicating that ovaries contribute about 50% of the total output of 3β-hydroxy-Δ5-steroids in treated, intact female rats. As late as 28 days after a single injection of cyanoketone 3β-hydroxy-Δ5-steroids (44 μg/24 h) are excreted in bile and the total excretion of corticosteroid metabolites is still low (72 μg/24 h) at this time. 130 days after a single dose, no 3β-hydroxy-Δ5-steroids can be identified in bile but the total corticosteroid excretion is still less than 2 standard deviations below values of untreated intact animals (315 μg/24 h). Thus, in females cyanoketone has both an immediate enzyme-inhibiting effect reflected by rapid onset of action after administration and, in addition, a long-term depressing action on enzyme biosynthesis manifested by low total steroid excretion values measured at least as long as 130 days after injection of inhibitor. Administration of cyanoketone to male rats gives rise to a small biliary excretion of 3β-hydroxy-Δ5-steroids (3β,16α-dihydroxy-5-pregnen-20-one, 5-pregnene-3β,17α,20α-triol and 5-pregnene-3β,20α-diol) and a decrease in corticosteroid (mainly 3β, 11β,21-trihydroxy-5α-pregnan-20-one) excretion. Corticosteroid output reaches normal values about 24 h after injection of inhibitor. Testectomy eliminates biliary 3β-hydroxy-Δ5-steroids. These findings indicate that cyanoketone produces biliary 3β-hydroxy-Δ5-steroids mainly of testicular origin. Moreover, it appears that the 3β-hydroxy-Δ5-steroid oxidoreductase system in the adrenals and testes of the male rat is inhibited by cyanoketone considerably less efficiently and for a shorter duration than that in the adrenals and ovaries of the female. [ABSTRACT FROM AUTHOR]