Omoto Yoko, Lathe Richard, Warner Margaret, Gustafsson Jan-Ake
Department of Medical Nutrition, Karolinska Institute, 141 86 Huddinge, Sweden.
Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2814-9. doi: 10.1073/pnas.0500198102. Epub 2005 Feb 14.
CYP7B1 is the enzyme responsible for hydroxylation and termination of the estrogenic actions of the androgen metabolite, 5alpha-androstane-3beta, 17beta-diol (3betaAdiol). 3betaAdiol is estrogenic in ERalpha or ERbeta positive cells only if they do not express CYP7B1. In this study we show that female CYP7B1(-/-) mice experience early onset of growth of the uterus and mammary glands and commence estrus cycles 2 days earlier than their wild-type littermates. Adult mammary glands and uteri appear to be under continuous estrogenic stimulation. We conclude that, by cell-specific regulation of the estrogenicity of 3betaAdiol, CYP7B1 performs two major tasks: (i) it allows 3betaAdiol to have growth inhibitory effects through ERbeta and (ii) it permits estradiol-specific activation of estrogen receptors by protection of certain cells from the estrogenic effects of 3betaAdiol. When CYP7B1 is inactivated, 3betaAdiol activates estrogen receptors indiscriminately, and the overall effect is prolonged and inappropriate exposure to estrogen.
细胞色素P450 7B1（CYP7B1）是一种负责雄激素代谢产物5α-雄甾烷-3β,17β-二醇（3β-二醇）雌激素作用的羟基化和终止的酶。只有在不表达CYP7B1的情况下，3β-二醇在雌激素受体α（ERα）或雌激素受体β（ERβ）阳性细胞中才具有雌激素活性。在本研究中，我们发现雌性CYP7B1基因敲除小鼠子宫和乳腺的生长提前开始，并且比其野生型同窝小鼠提前2天进入发情周期。成年小鼠的乳腺和子宫似乎受到持续的雌激素刺激。我们得出结论，通过对3β-二醇雌激素活性的细胞特异性调节，CYP7B1执行两项主要任务：（i）它使3β-二醇通过ERβ产生生长抑制作用；（ii）它通过保护某些细胞免受3β-二醇的雌激素作用，使雌二醇特异性激活雌激素受体。当CYP7B1失活时，3β-二醇会不加区分地激活雌激素受体，其总体效果是雌激素暴露时间延长且不适当。
