Modulation of Transforming and Clastogenic Activities of Catechol Estrogens by a Catechol-O-methyltransferase Inhibitor in Syrian Hamster Embryo Fibroblasts

Summary

Catechol estrogens (CEs) are considered critical intermediates in estrogen (E)-induced carcinogenesis. Previously, we demonstrated that estradiol (E₂), estrone (E₁), and four of their catechol estrogens, 2- and 4-OHE₂ and 2- and 4-OHE₁ induced morphological transformation in Syrian hamster embryo (SHE) cells, and their transforming activities varied as follows: 4-OHE₁ > 2-OHE₁ > 4-OHE₂ > 2-OHE₂ ≧ E₁, 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 of the CEs using SHE cells. The frequencies of transformation and chromosome aberrations induced by 4-OHE₁ were not affected by co-treatment with Ro-41-0960, but those induced by 2-OHE₁ were markedly enhanced. The frequency of transformation induced by 4-OHE₁ was markedly decreased by E₂ in a concentration dependent manner, but this decrease was not inhibited by Ro41-0960. Cell treatment with E₂, 2-OHE₁, or 4-OHE₁ alone induced apoptosis as detected by the TUNEL method. Additive effect on the induction of apoptosis was observed in cells treated with E₂ + 2-OHE₁ or 4-OHE₁. The % apoptotic cells induced by E₂ and 4-OHE₁ decreased in the presence of Ro41-0960, while those induced by E₂ and 2-OHE₁ did not. These results suggest an important role of both the substrate specificity of COMT and the induction of apoptosis in CE-induced carcinogenesis.