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In Vitro and in Vivo Regulation of Antioxidant Response Element-Dependent Gene Expression by Estrogens

Departments of Biochemistry (P.J.A., C.E.-N., B.J.P., M.H., D.B.L.), Veterinary Pathobiology (E.M.C., B.M.J.), Child Health (D.B.L.), and Animal Sciences (D.B.L.), MU Center for Phytonutrient and Phytochemical Studies (P.J.A., C.E.-N., E.M.C., B.M.J., B.J.P., D.B.L.), University of Missouri, Columbia, Missouri 65211

Address all correspondence and requests for reprints to: Dennis B. Lubahn, Ph.D., Room 110A, Animal Sciences Research Center, 920 East Campus Drive, University of Missouri, Columbia, Missouri 65211. E-mail: lubahnd{at}missouri.edu.

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 17ß-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 17ß-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 17ß-estradiol exposure in the uteri of mice. In conclusion, we have shown that 17ß-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.

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