Estrogens function as essential regulatory agents for a variety of reproductive processes. In human pregnancy, they are produced in wide variety and large quantities by the placenta, acting upon androgens provided by maternal and fetal synthesis. Estrogen production can thus provide an assessment of placental sufficiency and of fetal well-being and development. A major goal of this study is to characterize the biochemical basis for estrogen synthesis as an important aspect of placental function and additionally to provide knowledge relevant to the synthesis of estrogens carried out by ovary, testis, brain, breast, fat and other tissues. These studies are designed to identify, characterize, differentiate and isolate the membrane-bound oxidase species which are responsible for the synthesis of estrone, estradiol-17Beta, estradiol-17Alpha and estriol by the human placenta. Oxidase activities will be discriminated by selective or differential responses to a variety of agents to be utilized to characterize the specificity of substrate-binding sites, the reactivity of oxygen-activating sites and the properties of regulatory sites which contribute to the overall capacity for estrogen production displayed by placental membrane fractions. Agents to be utilized in these studies will include irreversibly inactivating substrate-analogs (""""""""suicide substrates""""""""), hemoprotein-liganding agents, estrogens and other steroids, and pharmacological agents. Chronic changes in oxidase activities in response to maternal smoking will also be utilized to evaluate the existence of independent oxidase species involved in selective estrogen synthesis. Solubilization, fractionation and isolation of membrane components will be employed to verify the physical existence of unique oxidase species and to further characterize their catalytic capabilities. Other oxygenation reactions directed against estrogens, drugs, carcinogenic hydrocarbons and other environmental pollutants are also carried out by placental membrane fractions responsible for estrogen synthesis. The relationship of these oxidase systems to those involved in estrogen synthesis will be examined using similar experimental approaches to determine whether common catalytic species or regulatory mechanisms are involved.
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