Differential regulation of cytochrome P450 1A1 and 1B1 by a combination of dioxin and pesticides in the breast tumor cell line MCF-7.
Dioxin and pesticides with xenoestrogenic activity are environmental contaminants that are suspected of promoting human diseases such as cancers. However, few studies have addressed the molecular consequences of a combination of these contaminants, a situation that is likely to occur in the environment. We investigated the effects of natural and xenoestrogens on basal and 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cytochrome P450 (CYP) 1A1 and 1B1. The CYP1B1/1A1 ratio is a critical determinant of the metabolism and toxicity of estradiol in mammary cells. Here we show that in MCF-7 cells, 17beta-estradiol and alpha-endosulfan can repress whole cell ethoxyresorufin-O-deethylase activity, lowering CYP1A1 mRNA levels as well as promoter activity as assessed by transient transfection assays. These negative effects are observed at both the basal and tetrachlorodibenzo-p-dioxin-induced levels. Under the same conditions, CYP1B1 mRNA levels and promoter activity are not affected. The effects on mRNA-induced levels are also observed in another mammary cell line, T47D, but not in mammary cell lines that do not express aryl hydrocarbon receptor and estrogen receptor (ER). Moreover, the use of ER antagonists shows that these effects are ER dependent in MCF-7 cells. In human hepatoma HepG2 cells, which lack functional ER, alpha-endosulfan, but not 17beta-estradiol, displays a repressive effect on CYP1A1 through a different mechanism. These results show that xenoestrogens, by altering the ratio of CYP1B1/CYP1A1, could redirect estradiol metabolism in a more toxic pathway in the breast cell line MCF-7.
Coumoul
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Institut National de la Santé et de la Recherche Médicale U490, Université René Descartes, 45 rue du Saints-Pères 75270 Paris Cedex, France.
Diry
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Robillot
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Barouki
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D001189:Aryl Hydrocarbon Hydroxylases; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004726:Endosulfan / Q000633:toxicity*; D004958:Estradiol / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006843:Hydrocarbons, Chlorinated; D007306:Insecticides / Q000633:toxicity*; D007700:Kinetics; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000502:physiology; D014407:Tumor Cells, Cultured
D006843:Hydrocarbons, Chlorinated; D007306:Insecticides; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D004726:Endosulfan