EFFECTS OF CIGARETTE SMOKING OR PCBS ON HUMAN ESTRADIOL

早期的研究表明，吸烟者有降低风险， 子宫内膜癌和骨质疏松症的风险增加 这被认为是由香烟的抑制作用引起的 吸烟对雌激素的影响一些但不是所有的研究表明 吸烟者血浆雌二醇水平较低， 增强这种雌激素的全身2-羟基化。一个主要重点 这项建议的目的是描述吸烟对 雌二醇向多羟基化的NADPH依赖性代谢 和酮代谢物，特别是， 肝外雌激素靶器官如子宫内膜， 胎盘此外，我们将描述多个 暴露妇女胎盘形成的雌二醇代谢物 多氯联苯（PCBs）和多氯联苯（PCBs） 二苯并呋喃类化合物， 单加氧酶我们建议的研究不仅应加强我们的 了解吸烟的抗雌激素作用， 妇女，但他们也应该为我们提供有用的信息， 细胞色素P450酶的诱导， 各种雌二醇代谢物的形成（包括雌激素- 活性和/或遗传毒性代谢物），以及 雌激素作用的人体靶器官。我们计划： （l）.确定依赖NADPH的雌二醇代谢物的特征 由吸烟者子宫内膜微粒体形成 和不吸烟的人 （2）.测定NADPH依赖性雌二醇代谢产物的谱 由吸烟者的胎盘微粒体形成， 不吸烟的人。 （3）.测定NADPH依赖性雌二醇代谢产物的谱 由吸烟者的肝微粒体形成， 不吸烟的人。 （4）.测定NADPH依赖性雌二醇代谢产物的谱 由意外暴露于 多氯联苯和多氯二苯并呋喃。 （5）.确定选择性抑制抗体对各种 细胞色素P450亚型在雌二醇代谢途径中的作用 在上述研究中观察到。 （6）.测定吸烟对浓度的影响 未代谢的雌二醇在人子宫内膜中的含量。

Earlier studies indicated that cigarette smokers have a decreased risk of uterine endometrial cancer and an increased risk of osteoporosis which are thought to be caused by an inhibitory effect of cigarette smoking on estrogen action. Some but not all studies have indicated that cigarette smokers have lower plasma levels of estradiol and enhanced systemic 2-hydroxylation of this estrogen. A major focus of this proposal is to characterize the effects of cigarette smoking on NADPH-dependent metabolism of estradiol to multiple hydroxylated and keto metabolites by human liver and, in particular, by extrahepatic estrogen target organs such as uterine endometrium and placenta. In addition, we will characterize the profile of multiple estradiol metabolites formed by placentas from women exposed accidentally to polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans which are potent inducers of microsomal monooxygenases. Our proposed studies should not only enhance our understanding of the antiestrogenic effect of cigarette smoking in women, but they should also provide us with useful information on the inducibility of cytochrome P450 enzymes that catalyzed the formation of various estradiol metabolites (including hormonally- active and/or genotoxic metabolites) in human liver as well as in human target organs for estrogen action. We plan to: (l).Determine the profile of NADPH-dependent estradiol metabolites formed by uterine endometrial microsomes from cigarette smokers and matched nonsmokers. (2).Determine the profile of NADPH-dependent estradiol metabolites formed by placental microsomes from cigarette smokers and matched nonsmokers. (3).Determine the profile of NADPH-dependent estradiol metabolites formed by liver microsomes from cigarette smokers and matched nonsmokers. (4).Determine the profile of NADPH-dependent estradiol metabolites formed by placental microsomes from women exposed accidentally to polychlorinated biphenyls and polychlorinated dibenzofurans. (5).Determine the effects of selective inhibitory antibodies to various cytochrome P450 isoforms on the pathways of estradiol metabolism observed in the studies described above. (6).Determine the effects of cigarette smoking on the concentration of unmetabolized estradiol in human uterine endometrium.