STIMULATION OF 17-BETA-ESTRADIOL METABOLISM IN MCF-7 CELLS BY BROMOCHLORO-SUBSTITUTED AND CHLOROMETHYL-SUBSTITUTED DIBENZO-P-DIOXINS AND DIBENZOFURANS - CORRELATIONS WITH ANTIESTROGENIC ACTIVITY

Mixed halo- and haloalkyl-substituted dibenzo-p-dioxins (DD) and diben zofurans (DF) are known environmental contaminants, although there is limited information on the toxic effects of these compounds in human c ells. In this study antiestrogenicity, a property of 2,3,7,8-Cl4-DD, w as investigated with a series of bromochloro- and chloromethyl-substit uted DDs and DFs. The effects of these compounds on the metabolism of 17 beta-estradiol (E2) and on the estrogen-dependent formation of mult icellular foci in cultures of MCF-7 human breast cells were examined. Pretreatment of MCF-7 cells with 2,3,7,8-Cl4-DD induced pathways of E2 metabolism involving cytochrome P-450-catalyzed hydroxylation, methyl ation of the catechol estrogens, and conjugation. Several Br-Cl3-DD an d Br2-Cl2-DD congeners with halogen substitution at the 2, 3, 7, and 8 positions also stimulated E2 metabolism with similar potency to that of 2,3,7,8-Cl4-DD; however, compounds with substitution of a methyl gr oup for a halogen at any of these positions did not stimulate the meta bolism of E2. For the series of compounds tested in MCF-7 cultures, a close correlation was observed between the antiestrogenicity as measur ed by the inhibition of estrogen-dependent postconfluent growth that r esults in focus formation and the efficacy with which the compounds st imulated the metabolism of E2. 2,3,7,8-TetrahaloDDs with one or two br omine atoms at these positions were highly antiestrogenic as determine d by their inhibition of estrogen-dependent focus formation, whereas t he methyl-substituted polychlorinated DDs and DFs investigated did not inhibit focus formation. These results indicate that the 2,3,7,8-subs tituted mixed halo-substituted DDs and DFs are of importance when the biologic effects of halogenated DD and DF congeners are considered, an d provide additional evidence for the role of increased metabolism of E2 in the antiestrogenic effects of halogenated DDs and DFs.