IMPACT OF TAMOXIFEN ON PERIPUBERTAL ANDROGEN IMPRINTING OF RAT HEPATIC CYTOCHROME-P450 2C11, CYTOCHROME-P450 3A2, AND STEROID 5-ALPHA-REDUCTASE

Expression of sex-dependent rat hepatic cytochromes P450 and steroid 5 alpha-reductase is regulated mainly by the sex-specific pattern of gr owth hormone (GH) secretion and is subject to androgen imprinting. Sin ce tamoxifen suppresses GH pulse amplitude and nadir levels, we invest igated the effect of tamoxifen on peripubertal testosterone imprinting of hepatic CYP2C11, CYP3A2, CYP2A1, and steroid 5 alpha-reductase. Pr epubertal tamoxifen administration (5 mg once daily s.c. on days 28 an d 29 of age) to non-ovariectomized female Sprague-Dawley rats did not affect hepatic microsomal CYP2C11-dependent testosterone 2 alpha-hydro xylase, CYP3A-mediated testosterone 6 beta-hydroxylase, CYP2A1-depende nt testosterone 7 alpha-hydroxylase, or steroid 5 alpha-reductase acti vity in adult rats. Testosterone treatment (5 mu mol/kg, s.c., once da ily) of intact female rats during either puberty (days 35-49 of age) o r adult life (days 69-77 of age) had no effect on these enzyme activit ies in adult (78 day-old) female rats, but the same treatment given du ring both of these periods induced the male-specific testosterone 2 al pha- and 6 beta-hydroxylase activities and suppressed the female-predo minant testosterone 7 alpha-hydroxylase and steroid 5 alpha-reductase activities, indicating that peripubertal testosterone administration i mprints the adult androgen responsiveness but not the basal levels of these enzyme activities in non-ovariectomized female rats. However, pe ripubertal androgen imprinting of the basal levels of testosterone 2 a lpha-hydroxylase and steroid 5 alpha-reductase activities was observed in female rats administered tamoxifen prepubertally. Tamoxifen pretre atment also enhanced testosterone imprinting of the adult androgen res ponsiveness of testosterone 2 alpha- and 6 beta-hydroxylase and steroi d 5 alpha-reductase activities. The enhanced testosterone hydroxylase activities were, however, not associated with an increase in microsoma l NADPH-cytochrome P450 reductase activity, but were accompanied by el evated hepatic CYP2C11 and CYP3A2 protein levels. Overall, the present study indicates that prepubertal tamoxifen administration does not in terfere with the normal sex differentiation of the gender-dependent he patic cytochromes P450 and steroid 5 alpha-reductase, but this drug mo dulates peripubertal androgen imprinting of CYP2C11, CYP3A2, and stero id 5 alpha-reductase in adult female rats.