MECHANISM OF ACTION OF 2,3,7,8-TCDD AND 6-METHYL-1,3,8-TRICHLORODIBENZOFURAN (MCDF) AS ANTIESTROGENS IN THE FEMALE RAT
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abstract
Several studies have reported that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) acts as an antiestrogen in rodents and human breast cancer MCF-7 cells in culture. It has been proposed that these effects may be related to the induction of estradiol-2-hydroxylase activity which effects a decrease in cellular estradiol levels due to increased metabolism. This study reports the comparative antiestrogenic effects of TCDD and 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) on cytosolic and nuclear estrogen and progesterone receptor levels in both the rat uterus and liver. MCDF, like TCDD, acted as an antiestrogen in the female rat, causing a dose-response decrease in uterine and hepatic cytosolic and nuclear estrogen and progesterone receptor levels; both compounds also antagonized the estradiolinduced increase in uterine wet weights. TCDD was 300 to 700 times more potent than MCDF as an antiestrogen, however the TCDD/MCDF potency ratios as inducers of hepatic monooxygenases were > 150,000. Moreover, the antiestrogenic effects of MCDF were observed at doses which caused minimal induction of hepatic monooxygenases. These results suggest that the antiestrogenicity of TCDD and related compounds is not due to increased metabolism of estradiol. 1989.
