COVALENT INTERACTIONS OF ESTROGENS IN TARGET TISSUES

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To understand the role of metabolism of estradiol in the biology of the hormone it is essential to know the biological effects of its diverse metabolic products. This project is concerned with the cellular interactions of 16Alpha-hydroxyestrone and 2-hydroxyestrone, major metabolites of estradiol with biological properties distinct from those of the parent hormone. 16Alpha-hydroxyestrone forms covalent linkages with primary amino groups via Schiff base formation and subsequent Heyns rearrangement. 2-Hydroxyestrone reacts avidly with nucleophiles such as sulfhydryl groups to also form covalent bonds with biological molecules. Both processes have been shown to proceed with cellular components in vitro and in vivo and are considered to be of importance in the physiology and pathophysiology of estrogen action. Precise information will be sought on the subcellular sites of such covalent bond formation in estrogen target tissues and on the nature of the specific biological macromolecules involved in these interactions. The biological consequence of these processes will be explored in in vitro and in vivo studies employing appropriate experimental models. It is expected that these studies will shed light on the role of these natural estrogens in hormonally linked diseases.