Differential regulation of cytochrome p450 1A1 and 1B1 by a combination ofdioxin and pesticides in the breast tumor cell line MCF-7

Dioxin and pesticides with xenoestrogenic activity are environmental contam inants that are suspected of promoting human diseases such as cancers. Howe ver, few studies have addressed the molecular consequences of a combination of these contaminants, a situation that is likely to occur in the environm ent, We investigated the effects of natural and xenoestrogens on basal and 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cytochrome P450 (CYP) 1A1 and 1 B1, The CYP1B1/1A1 ratio is a critical determinant of the metabolism and to xicity of estradiol in mammary cells. Here we show that in MCF-7 cells, 17 beta -estradiol and alpha -endosulfan can repress whole cell ethoxyresorufi n-O-deethylase activity, lowering CYP1A1 mRNA levels as well as promoter ac tivity as assessed by transient transfection assays. These negative effects are observed at both the basal and tetrachlorodibenzo-p-dioxin-induced lev els. Under the same conditions, CYP1B1 mRNA levels and promoter activity ar e not affected. The effects on mRNA-induced levels are also observed in ano ther mammary cell line, T47D, but not in mammary cell lines that do not exp ress aryl hydrocarbon receptor and estrogen receptor (ER), Moreover, the us e of ER antagonists shows that these effects are ER dependent in MCF-7 cell s. In human hepatoma HepG2 cells, which lack functional ER, alpha -endosulf an, but not 17 beta -estradiol, displays a repressive effect on CYP1A1 thro ugh a different mechanism. These results show that xenoestrogens, by alteri ng the ratio of CYP1B1/CYP1A1, could redirect estradiol metabolism in a mor e toxic pathway in the breast cell line MCF-7.