title: In vitro and in vivo regulation of antioxidant response element-dependent gene expression by estrogens.
abstract: Understanding estrogen's regulation of phase II detoxification enzymes is important in explaining how estrogen exposure increases the risk of developing certain cancers. Phase II enzymes such as glutathione-S-transferases (GST) and quinone reductase protect against developing chemically induced cancers by metabolizing reactive oxygen species. Phase II enzyme expression is regulated by a cis-acting DNA sequence, the antioxidant response element (ARE). It has previously been reported that several antiestrogens, but not 17beta-estradiol, could regulate ARE-mediated gene transcription. Our goal was to determine whether additional estrogenic compounds could regulate ARE-mediated gene expression both in vitro and in vivo. We discovered that physiological concentrations (10 nm) of 17beta-estradiol repressed GST Ya ARE-dependent gene expression in vitro. Treatment with other endogenous and anti-, xeno-, and phytoestrogens showed that estrogen receptor/ARE signaling is ligand, receptor subtype, and cell type specific. Additionally, GST and quinone reductase activities were significantly lowered in a dose-dependent manner after 17beta-estradiol exposure in the uteri of mice. In conclusion, we have shown that 17beta-estradiol, and other estrogens, down-regulate phase II enzyme activities. We propose estrogen-mediated repression of phase II enzyme activities may increase cellular oxidative DNA damage that ultimately can result in the formation of cancer in some estrogen-responsive tissues.
authors.affiliation: Department of Biochemistry, MU Center for Phytonutrient and Phytochemical Studies, University of Missouri, Columbia, Missouri 65211, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Ansell
authors.forename: C
authors.initials: C
authors.lastname: Espinosa-Nicholas
authors.forename: E M
authors.initials: EM
authors.lastname: Curran
authors.forename: B M
authors.initials: BM
authors.lastname: Judy
authors.forename: B J
authors.initials: BJ
authors.lastname: Philips
authors.forename: M
authors.initials: M
authors.lastname: Hannink
authors.forename: D B
authors.initials: DB
authors.lastname: Lubahn
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000502:physiology*; D001483:Base Sequence; D001943:Breast Neoplasms; D019556:COS Cells; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D007529:Isoflavones / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D048789:Phytoestrogens; D028321:Plant Preparations / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D014162:Transfection
chemical_list: D000975:Antioxidants; D004967:Estrogens; D007529:Isoflavones; D048789:Phytoestrogens; D028321:Plant Preparations; D011960:Receptors, Estrogen; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase