Chang T K, Chan M M, Holsmer S L, Bandiera S M, Bellward G D
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Biochem Pharmacol. 1996 Feb 9;51(3):357-68. doi: 10.1016/0006-2952(95)02191-4.
Expression of sex-dependent rat hepatic cytochromes P450 and steroid 5 alpha-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 5 alpha-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 2 alpha-hydroxylase, CYP3A-mediated testosterone 6 beta-hydroxylase, CYP2A1-dependent testosterone 7 alpha-hydroxylase, or steroid 5 alpha-reductase activity in adult rats. Testosterone treatment (5 mumol/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 2 alpha- and 6 beta-hydroxylase activities and suppressed the female-predominant testosterone 7 alpha-hydroxylase and steroid 5 alpha-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 2 alpha-hydroxylase and steroid 5 alpha-reductase activities was observed in female rats administered tamoxifen prepubertally. Tamoxifen pretreatment also enhanced testosterone imprinting of the adult androgen responsiveness of testosterone 2 alpha- and 6 beta-hydroxylase and steroid 5 alpha-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 5 alpha-reductase, but this drug modulates peripubertal androgen imprinting of CYP2C11, CYP3A2, and steroid 5 alpha-reductase in adult female rats.
性别的大鼠肝细胞色素P450和类固醇5α-还原酶的表达主要受生长激素（GH）分泌的性别特异性模式调节，并受到雄激素印记的影响。由于他莫昔芬会抑制GH脉冲幅度和最低点水平，我们研究了他莫昔芬对青春期前肝脏CYP2C11、CYP3A2、CYP2A1和类固醇5α-还原酶的青春期睾酮印记的影响。对未切除卵巢的雌性Sprague-Dawley大鼠青春期前给予他莫昔芬（5mg，每日一次，皮下注射，在28和29日龄时），并不影响成年大鼠肝脏微粒体中CYP2C11依赖性睾酮2α-羟化酶、CYP3A介导的睾酮6β-羟化酶、CYP2A1依赖性睾酮7α-羟化酶或类固醇5α-还原酶的活性。在青春期（35 - 49日龄）或成年期（69 - 77日龄）对完整雌性大鼠进行睾酮处理（5μmol/kg，皮下注射，每日一次），对成年（78日龄）雌性大鼠的这些酶活性没有影响，但在这两个时期都给予相同处理会诱导雄性特异性的睾酮2α-和6β-羟化酶活性，并抑制雌性占优势的睾酮7α-羟化酶和类固醇5α-还原酶活性，这表明青春期给予睾酮会印记成年期的雄激素反应性，但不会影响未切除卵巢的雌性大鼠这些酶活性的基础水平。然而，在青春期前给予他莫昔芬的雌性大鼠中观察到了青春期雄激素对睾酮2α-羟化酶和类固醇5α-还原酶基础活性水平的印记。他莫昔芬预处理还增强了睾酮对成年期睾酮2α-和6β-羟化酶以及类固醇5α-还原酶活性的雄激素反应性的印记。然而，增强的睾酮羟化酶活性与微粒体NADPH-细胞色素P450还原酶活性的增加无关，而是伴随着肝脏CYP2C11和CYP3A2蛋白水平的升高。总体而言，本研究表明青春期前给予他莫昔芬不会干扰性别依赖性肝细胞色素P450和类固醇5α-还原酶的正常性别分化，但这种药物会调节成年雌性大鼠青春期睾酮对CYP2C11、CYP3A2和类固醇5α-还原酶的印记。
