Estrogen Regulation of Antioxidant Response Element-Dependent Gene Expression

Dennis B. Lubahn, Ph.D. and Mark Hannink, Ph.D.
University of Missouri
R01ES08272, P01ES10535, and R21ES11721

Background: Exposure to chemicals that cause oxidative stress can greatly affect the development of many diseases including cancer. The metabolism of many chemicals has proven to be effective in modulating the degree of oxidative damage. The metabolism of many chemicals involves two distinct types of enzymes known as phase I and phase II.

Phase I enzymes, members of the cytochrome P450 superfamily, metabolically oxidize many chemicals thereby forming intermediates. Phase II detoxification enzymes, such as glutathione-s-transferases and quinone reductase, which are responsible for metabolizing the products of phase I metabolic reactions, degrade these reactive intermediates by conjugation or reduction reactions, thereby protecting cells from oxidative DNA damage.

Understanding how estrogens regulate phase II detoxification enzymes is important in explaining how estrogen exposure increases the risk of developing certain cancers like breast cancer. Phase II enzyme expression is regulated by a DNA sequence known as the antioxidant response element. These researchers sought to determine whether 17beta-estradiol could regulate the antioxidant response element-dependent gene expression.

Advance: Results indicate that estradiol did repress glutathione gene expression. Additionally, glutathione and quinone reductase activities were significantly lowered in a dose-dependent manner after estradiol exposure in the uteri of mice.

Implication: These experiments conclude that 17beta-estradiol and other estrogens down regulate phase II enzyme activities. This repression may increase cellular oxidative DNA damage that ultimately can result in the formation of cancer in estrogen-responsive tissues like the breast and female reproductive organs.

Citation: Ansell PJ, Espinosa-Nicholas C, Curran EM, Judy BM, Philips BJ, Hannink M, Lubahn DB. In vitro and in vivo regulation of antioxidant response element-dependent gene expression by estrogens. Endocrinology. 2004 Jan;145(1):311-7.