CIGARETTE SMOKING OR PCBS EFFECTS ON ESTRADIOL

早期的研究表明，吸烟者的风险较低。 子宫内膜癌和骨质疏松症风险增加 它们被认为是由香烟的抑制作用引起的 吸烟对雌激素的作用。一些(但不是所有)研究表明 吸烟者的血浆雌二醇水平较低 增强这种雌激素的全身性2-羟基化。一个主要的焦点 这项建议的目的是刻画吸烟对健康的影响 依赖NADPH的雌二醇向多羟化的代谢 和酮类代谢物通过人体肝脏，特别是通过 肝外雌激素靶器官，如子宫内膜和 胎盘。此外，我们还将描述多个 暴露于胎盘的女性胎盘形成的雌二醇代谢产物 意外地将多氯联苯(PCbs)和多氯化 二苯并呋喃是一种有效的微粒体诱导剂 单加氧酶。我们建议的研究不仅应加强我们的 对吸烟抗雌激素作用的认识 女性，但她们也应该为我们提供关于 催化细胞色素P450酶的诱导性 形成各种雌二醇代谢物(包括荷尔蒙- 活性和/或遗传毒性代谢物) 人体雌激素作用的靶器官。我们计划： (L).NADPH依赖的雌二醇代谢物的测定 由吸烟者子宫内膜微粒子形成 并匹配了不吸烟的人。 (2)NADPH依赖的雌二醇代谢物的测定 由吸烟者的胎盘微粒形成，并与之匹配 非吸烟者。 (3)NADPH依赖的雌二醇代谢物的测定 由吸烟者的肝微粒形成，并与之匹配 非吸烟者。 (4)NADPH依赖的雌二醇代谢物的测定 由意外接触的女性胎盘微粒子形成 多氯联苯和多氯二苯并呋喃。 (5).测定选择性抑制抗体对不同类型动物的影响 雌二醇代谢途径中的细胞色素P450亚型 在上述研究中观察到的。 (6).测定吸烟对血药浓度的影响 人子宫内膜中未代谢雌二醇的含量。

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.