雌激素暴露与代谢基因表达
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Estrogen Exposure and Metabolic Gene Expression
Ansell PJ, Espinosa-Nicholas C, Curran EM, Judy BM, Philips BJ, Hannink M, Lubahn DB. 2004. In vitro and in vivo regulation of antioxidant response element-dependent gene expression by estrogens. Endocrinology 145:311-317.
Exposure to chemicals that cause oxidative stress can contribute to the development of many diseases, including cancer. Many times, however, the metabolism of such chemicals has proven to be effective in modulating the degree of oxidative damage. In this paper, NIEHS grantee Dennis B. Lubahn and colleagues from the University of Missouri-Columbia explore how estrogen exposure affects enzyme expression during phase II of metabolism. Understanding how estrogens regulate phase II detoxification enzymes is important in explaining why estrogen exposure increases the risk of developing breast, ovarian, and uterine cancers.
The metabolism of many chemicals involves two distinct phases, each with characteristic enzymes. Phase I enzymes 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. Phase II enzyme expression is regulated by a DNA sequence known as the antioxidant response element.
The Missouri researchers sought to determine whether and how 17?-estradiol regulates gene expression that depends upon the antioxidant response element. Their results indicate that 17?-estradiol repressed glutathione-S-transferase gene expression. Additionally, glutathione-S-transferase and quinone reductase activities in the mouse uterus were significantly lowered in a dose-dependent manner following 17?-estradiol exposure.
The researchers conclude that 17?-estradiol and other estrogens can downregulate phase II enzyme activities in the uterus, thus potentially slowing the metabolism of reactive intermediates. This repression may increase cellular oxidative DNA damage that ultimately can result in the formation of cancer in estrogen-responsive tissues such as the breast and female reproductive organs.
Jerry Phelps