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 substitutents and include: 6-methyl-1,3,8-triCDF, 6-ethyl-1,3,8-triCDF, 6-n-propyl-1,3,8-triCDF, 6-i-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-1,3,7-triCDF, and 8-methyl-1,2,4,7-tetraCDF (three lateral substituents); 8-methyl-2,3,7-triCDF, 8-methyl-2,3,4,7-tetraCDF (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 estrogen 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 ED50 values for antiestrogenicity were similar for the three compounds; however, the ED50 values for induction of hepatic CYP1A1-dependent activity were 73,600 (estimated), 8.52, and 5.31 mumol/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 ED50 (induction)/ED50 (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.
Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466, USA.
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D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D008862:Microsomes, Liver / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
D001572:Benzofurans; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1