STUDIES ON THE CONVERSION OF ANDROGENS TO ESTROGENS BY AROMATASE

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The levels of estrogen and possibly their oxidative metabolites play an important role in certain endocrine-dependent cancers. We are studying the enzymes responsible for estrogen synthesis and metabolism. Aromatase is the cytochrome P450 responsible for the conversion of androgens to estrogens. This conversion requires three sequential oxidations and the level of intermediate products released from the enzyme varies. We have shown that the intermediate profile is a function of the rate of enzyme reduction. Very large differences in the intermediate profiles between rat ovary and human placenta suggests that reduction rate may have a regulatory role. Another area of interest is the mechanism of aromatase. Although the enzyme has been studied for more than 20 years, the mechanism of the third oxidation is still unknown. An understanding of this mechanism can help in the development of mechanism-based aromatase inhibitors. Aromatase inhibitors are being considered for treatment of breast cancer and benign prostate hyperplasia. We are using both theoretical calculations and experimental techniques to study possible mechanisms of aromatase. Finally, we have begun a study to quantitate both estrogen synthesis and metabolism in various human tissues. In addition to estrogens, it has also been proposed that the level of 16alpha-hydroxyestrogens may be an important determinant in breast cancer. We are characterizing aromatase activity (including intermediates) and oxidative estrogen metabolism in human breast, ovarian, endometrial cervical, placental and adipose tissues.