Neonatal Imprinting of Liver Microsomal Hydroxylation and Reduction of Steroids

Abstract

Abstract The metabolism of 4-[4-14C]androstene-3,17-dione, 4-[4-14C]pregnene-3,20-dione, 5α-[4-14C]androstane-3α,17β-diol, 4,16-[7α-3H]androstadien-3-one, [4-14C]cholesterol, and 7α-hydroxy-4-[6β-3H]cholesten-3-one was studied in the microsomal fraction of livers from adult male and female rats which had been castrated neonatally or postpubertally. The effect of testosterone propionate treatment on postpubertally castrated male and female rats was also studied with respect to the hepatic microsomal metabolism of the mentioned steroid substrates. It was found that the different microsomal enzyme activities could be grouped into three categories according to their specific characteristics. One category of enzymes (represented by the 2β-hydroxylase active on 5α-androstane-3α,17β-diol, the 6β-hydroxylase active on 4-androstene-3,17-dione and 4-pregnene-3,20-dione, and the 18-hydroxylase active on 5α-androstane-3α, 17β-diol) was more active in male than in female rats. This sexual difference was completely abolished both by postpubertal and neonatal testectomy. The activities of the enzymes in this group were stimulated by treatment with testosterone propionate. A second category of enzymes (the 2α-hydroxylase active on 4-pregnene-3,20-dione and 5α-androstane-3α,17β-diol, the 16α-hydroxylase active on 4-androstene-3,17-dione, the Δ16-C19 steroid epoxidase active on 4,16-androstadien-3-one, and the 17β-hydroxysteroid reductase active on 4-androstene-3,17-dione) was generally much more active in male than in female rats. Only neonatal testectomy completely abolished this sexual difference, whereas postpubertal testectomy reduced but did not abolish the differences in enzyme activities between male and female rats. Testosterone propionate treatment led to increased activities of these enzymes. The third category of enzymes (the 7α-hydroxylase active on 4-androstene-3,17-dione and cholesterol, the 12α-hydroxylase active on 7α-hydroxy-4-cholesten-3-one, and the 16α-hydroxylase active on 4-pregnene-3,20-dione) was generally slightly more active in female than in male rats. The activities of the enzymes in this group were not significantly affected by neonatal or postpubertal gonadectomy or by treatment with testosterone propionate. Based on these findings the microsomal steroid-metabolizing enzyme activities may be grouped into three classes with regard to the mechanisms regulating their activity: (a) enzymes with a basal activity level regulated by nongonadal factors but reversibly inducible by androgens; (b) enzymes irreversibly imprinted or programmed by androgens during the prepubertal period and reversibly stimulated by androgens postpubertally; and (c) enzymes primarily regulated by nongonadal factors and only slightly affected by androgens. The 5α-reductase active on 4-androstene-3,17-dione, 4-pregnene-3,20-dione and 7α-hydroxy-4-cholesten-3-one is basally regulated by nongonadal factors in both male and female rats. In addition, the activity of this enzyme in male rats, which is about 8 to 10 times lower than that in female rats, is suppressed by testicular androgens by two mechanisms: (a) irreversibly by prepubertal imprinting or programming; and (b) reversibly by postpubertal suppression.