Catechol estrogens (CEs) are considered critical intermediates in estrogen (E)-induced carcinogenesis. Previously, we demonstrated that estradiol (E2), estrone (Ej), and four oftheir catechol estrogens, 2- and4-OHE2and 2- and 4-OHE, induced morphological transformation in Syrian hamster embryo (SHE) cells, and their transforming activities varied as follows: 4-OHEi > 2-OHE, > 4-OHE2 > 2-OHE2 > E,, E2, which are consistent with the genetic effects, i.e., chromosome aberrations and DNA adduct formation, of each E. To further elucidate the mechanism of hormonal carcinogenesis, we studied the effect of the catechol-O-methyltransferase (COMT) inhibitor Ro41-0960 on the transforming and clastogenic activities ofthe CEs using SHE cells. The frequencies oftransformation and chromosome aberrations induced by 4-OHE i were not affected by co-treatment with Ro-41 -0960, but those induced by 2-OHE] were markedly enhanced. The frequency of transformation induced by 4-OHE i was markedly decreased by E2 in a concentration dependent manner, but this decrease was not inhibited by Ro41-0960. Cell treatment with E2, 2-or alone induced apoptosis as detected by the TUNEL

method. Additive effect on the induction of apoptosis was observed in cells treated with E2 + 2-OHE! or 4-OHE). The % apoptotic cells induced by E2and 4-OHE, decreased in the presence of Ro41-0960, while those induced by and did not. These results suggest an important role of both the substrate specificity of COMT and the induction of apoptosis in CE-induced carcinogenesis.

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