Peripubertal defeminization of hepatic cytochromes P-450 2C11 and 3A2 by testicular steroids in the absence of neonatal defeminization

Avery, Jennifer Lea (1998) Peripubertal defeminization of hepatic cytochromes P-450 2C11 and 3A2 by testicular steroids in the absence of neonatal defeminization. Masters thesis, Memorial University of Newfoundland.

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Abstract

We studied the ability of testicular secretions to either defeminize (represented as an increase in basal specific activity), or masculinize (represented as an ability to respond to adult testosterone administration), the sex-specific P-450s 2C11 and 3A2, in the absence of neonatal defeminization. Neonatal defeminization of these P-450s is suspected to occur via androgen-derived estrogens. Defeminization was successfully prevented by subcutaneous insertion of Silastic™ capsules containing the aromatase blocker l,4,6-androstatriene-3,17-dione (ATD), from day 0 (birth) to day 21 (weaning), in the male rat The testes remained in situ from birth to day 21,35,55, 70, or death. Animals castrated on day 21 or 55 received either testosterone therapy (2 mg/kg/day, s.c, in corn oil) for 14 days, beginning on day 70, or received no testosterone therapy. All animals were killed on day 70 or 84. -- The neonatal ATD treatment blocked the normal increase in basal ethylmorphine demethylase (EMDM), 6β-hydroxylase, 2α-hydroxylase, and 16α-hydroxylase specific activity, seen in adulthood. Although ATD prevented the neonatal defeminization as noted by a permanent increase in basal activity, both P-450 isozymes were responsive to testosterone in adulthood, either partially (EMDM), or completely (6α, 2α-, 16α-hydroxylase). -- The intact testes from birth to death, in the ATD-treated male, effected a permanent increase in the basal activities of EMDM, as well as the 6β-, 2α-, and 16α-hydroxylations on testosterone. This treatment also effected a 100% recovery (i.e. intact male activity) of EMDM activity, when stimulated by testosterone in adulthood. The permanent increase in EMDM basal activity, is most likely completed by day 55, as there was no difference in specific activity between the day 55 castrate, and the day 70 castrate. Of the hydroxylations of testosterone, we demonstrate that castration on day 55 results in significantly higher specific activities of these isozymes, then castration on day 70. -- We also report significant sex differences (males > females) in aniline hydroxylase activity, cytochrome P-450 content, and cytochrome c reductase activity. We do not attribute the above results to differences in P-450 content or reductase activity. The 7α-hydroxylation of testosterone (P-450 2A1) was sexually differentiated (females > males). We demonstrated that the elimination of estrogens throughout the life of the male (ATD treated and castrated on day 21), prevented the feminization (increase in basal activity) of 7α-hydroxylase, following castration. -- These results demonstrate that puberty is a very dynamic process, resulting in changing characteristics of these sex-specific P-450s. Puberty is also a time when these basal enzyme activities, as well as the responsiveness of EMDM to adult testosterone therapy, can be permanently defeminized, in the absence of neonatal defeminization.

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