Stimulation of 17 beta-estradiol metabolism in MCF-7 cells by bromochloro- and chloromethyl-substituted dibenzo-p-dioxins and dibenzofurans: correlations with antiestrogenic activity.
Mixed halo- and haloalkyl-substituted dibenzo-p-dioxins (DD) and dibenzofurans (DF) are known environmental contaminants, although there is limited information on the toxic effects of these compounds in human cells. In this study antiestrogenicity, a property of 2,3,7,8-Cl4-DD, was investigated with a series of bromochloro- and chloromethyl-substituted DDs and DFs. The effects of these compounds on the metabolism of 17 beta-estradiol (E2) and on the estrogen-dependent formation of multicellular 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, methylation of the catechol estrogens, and conjugation. Several Br-Cl3-DD and 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 group for a halogen at any of these positions did not stimulate the metabolism of E2. For the series of compounds tested in MCF-7 cultures, a close correlation was observed between the antiestrogenicity as measured by the inhibition of estrogen-dependent postconfluent growth that results in focus formation and the efficacy with which the compounds stimulated the metabolism of E2. 2,3,7,8-TetrahaloDDs with one or two bromine atoms at these positions were highly antiestrogenic as determined by their inhibition of estrogen-dependent focus formation, whereas the methyl-substituted polychlorinated DDs and DFs investigated did not inhibit focus formation. These results indicate that the 2,3,7,8-substituted mixed halo-substituted DDs and DFs are of importance when the biologic effects of halogenated DD and DF congeners are considered, and provide additional evidence for the role of increased metabolism of E2 in the antiestrogenic effects of halogenated DDs and DFs.
Spink
D C
DC
Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany 12201-0509.
Johnson
J A
JA
Connor
S P
SP
Aldous
K M
KM
Gierthy
J F
JF
D001572:Benzofurans / Q000494:pharmacology*; D002478:Cells, Cultured; D015536:Down-Regulation; D004785:Environmental Pollutants / Q000494:pharmacology*; D004958:Estradiol / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001572:Benzofurans; D004785:Environmental Pollutants; D004965:Estrogen Antagonists; D006846:Hydrocarbons, Halogenated; D000072317:Polychlorinated Dibenzodioxins; D004958:Estradiol