Alkyl polychlorinated dibenzofurans and related compounds as antiestrogens in the female rat uterus: Structure-activity studies

The antiestrogenic activity of a series of alkyl-substituted polychlorinated dibenzofurans (PCDFs) were determined in the immature female Sprague-Dawley rat uterus. The compounds utilized in this study contain two, three, or four lateral substituents and include: 6-methyl-1,3,8-triCDF, 6-ethyl-1,3,8-triCDF, 6-t-propyl-1,3,8-triCDF, 6-t-propyl-1,3,8-triCDF, 6-t-butyl-1,3,8-triCDF, 8-methyl-1,3,6-triCDF (two lateral substituents); 6-methyl-2,3,8-triCDF, 6-methyl-2,3,4,8-tetraCDF, 8-methyl-2,3,7-triCDF, and 8-methyl-2,3,4,7-tetraCDF (three lateral substituents); 8-methyl-2,3,7-triCDF, 8-methyl-2,3,4,7-tet raCDF (four lateral substituents). Two additional compounds, 8-methyl-2,3,7-trichlorodibenzo-p-dioxin and 8-methyl-2,3;7-tribromodibenzo-p-dioxin (four lateral substituents), were also utilized. All of the alkyl-substituted compounds inhibited estrogen-induced uterine wet weight increase and cytosolic and nuclear progesterone and eshrogen receptor binding. The effects of structure on the antiestrogenic potencies were determined using 6-i-propyl-1,3,8-triCDF, 6-methyl-2,3,4,8-tetraCDF, and 8-methyl-2,3,4;7-tetraCDF as representative congeners containing two, three, and four lateral substituents, respectively. The ED(50) values for antiestrogenicity were similar for the three compounds; however, the ED(50) values for induction of hepatic CYP1A1-dependent activity were 73,600 (estimated), 8.52, and 5.31 mu mol/kg for 6-i-propyl-1,3,8-triCDF, 6-methyl-2,3,4,8-tetraCDF, and 8-methyl-2,3,4,7-tetraCDF, respectively. Since CYP1A1 can be used as a surrogate for toxic potency in the rat then high ED(50) (induction)/ED(50) (antiestrogenicity) ratios would be indicative of low toxicity and high antiestrogenic potency. The ratio was 13,990 to 17,100 for 6-i-propyl-1,3,8-triCDF, whereas the corresponding value for the compounds with three or four lateral substituents varied from 0.64 to 3.34. The results suggests that the 1,3,6,8-substituted alkyl PCDFs are useful structural models for developing new aryl hydrocarbon receptor-mediated antiestrogens for future clinical use as antiestrogens. (C) 1996 Academic Press, Inc.