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.
