Impact of tamoxifen on peripubertal Androgen imprinting of rat hepatic cytochrome P450 2C11, cytochrome P450 3A2, and steroid 5α-reductase

Abstract

Expression of sex-dependent rat hepatic cytochromes P450 and steroid 5α-reductase is regulated mainly by the sex-specific pattern of growth hormone (GH) secretion and is subject to androgen imprinting. Since tamoxifen suppresses GH pulse amplitude and nadir levels, we investigated the effect of tamoxifen on peripubertal testosterone imprinting of hepatic CYP2C11, CYP3A2, CYP2A1, and steroid 5α-reductase. Prepubertal tamoxifen administration (5 mg once daily s.c. on days 28 and 29 of age) to non-ovariectomized female Sprague-Dawley rats did not affect hepatic microsomal CYP2C11-dependent testosterone 2α-hydroxylase, CYP3A-mediated testosterone 6β-hydroxylase, CYP2A1-dependent testosterone 7α-hydroxylase, or steroid 5αreductase activity in adult rats. Testosterone treatment (5 μmol/kg, s.c., once daily) of intact female rats during either puberty (days 35–49 of age) or adult life (days 69–77 of age) had no effect on these enzyme activities in adult (78-day-old) female rats, but the same treatment given during both of these periods induced the male-specific testosterone 2α- and 6β-hydroxylase activities and suppressed the female-predominant testosterone 7α-hydroxylase and steroid 5α-reductase activities, indicating that peripubertal testosterone administration imprints the adult androgen responsiveness but not the basal levels of these enzyme activities in non-ovariectomized female rats. However, peripubertal androgen imprinting of the basal levels of testosterone 2α-hydroxylase and steroid 5α-reductase activities was observed in female rats administered tamoxifen prepubertally. Tamoxifen pretreatment also enhanced testosterone imprinting of the adult androgen responsiveness of testosterone 2α- and 6β-hydroxylase and steroid 5α-reductase activities. The enhanced testosterone hydroxylase activities were, however, not associated with an increase in microsomal NADPH-cytochrome P450 reductase activity, but were accompanied by elevated hepatic CYP2C11 and CYP3A2 protein levels. Overall, the present study indicates that prepubertal tamoxifen administration does not interfere with the normal sex differentiation of the gender-dependent hepatic cytochromes P450 and steroid 5α-reductase, but this drug modulates peripubertal androgen imprinting of CYP2C11, CYP3A2, and steroid 5α-reductase in adult female rats.