To examine a possible mechanism of endogenous
estrogen-induced
carcinogenesis, we studied the effect of the
catechol-O-methyltransferase (COMT) inhibitor
Ro 41-0960 on cell transforming and clastogenic activities of 2
catechol estrogens 2- and
4-hydroxyestrone (2- or 4-OHE1) using Syrian hamster embryo (SHE) cells. COMT activity was assayed by determining the methylation of 2- or 4-OHE1 using gas chromatography. The production of
2-methoxyestrone in cultures treated with 2-OHE1 was approximately 2-fold that of 4-methoxyestrone in cultures treated with 4-OHE1. 4-OHE1 induced morphological transformation at a higher frequency than 2-OHE1 did and the frequencies of cell transformation and
chromosome aberrations were not significantly changed in cells treated with 4-OHE1 in the presence of
Ro 41-0960. In contrast, the frequencies of cell transformation and
chromosome aberrations were markedly increased in cells treated with 2-OHE1 along with
Ro 41-0960 when compared to cells treated with 2-OHE1 alone. In addition, both
catechol estrogens induced P53
protein expression and apoptosis. The frequencies of apoptotic cells induced by the
catechol estrogens were modified by the COMT inhibition in a manner similar to those observed with the
chromosome aberrations assay and the cell transformation assay, indicating that each effect by the
catechol estrogens at the three measured endpoints might be caused by a mechanism similar to the others. Our findings indicate that COMT activity has an influence on cell transforming activity and its related genetic effects of
catechol estrogens in SHE cells, which implies that an individual activity of COMT may be one of the etiological factors in endogenous
estrogen-induced
carcinogenesis.