Inhibitory Effects of Nitrative Stress on the Sulfation of 17β-Estradiol and 4-Methoxyestradiol by Human MCF 10A Mammary Epithelial Cells

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Prolonged exposure to high level of estrogen is a known risk factor for breast carcinogenesis. It has been suggested recently that nitrative stress may be an etiologic factor for breast carcinogenesis. Since sulfation plays a major role in the homeostasis of estrogens and their metabolites, we attempted in the present study to find out whether nitrative stress may affect the homeostasis of estrogens through sulfation. Metabolic labeling experiments revealed that the amount of sulfated 17β-estradiol or 4-methoxyestradiol decreased dramatically in MCF-10A mammary epithelial cells incubated in the presence of 3-morpholinosydnonimine (SIN-1) or diethylenetriamine NONOate (DETA NONOate), two nitric oxide donors commonly used to simulate nitrative stress conditions. In searching for the mechanism underlying the decrease of the sulfation of 17β-estradiol and 4-methoxyestradiol, we demonstrated in an in vitro nitration experiment, that the human cytosolic sulfotransferase isoform 1E1 (SULT1E1), a major estrogen-sulfating enzyme, lost its estrogen-sulfating activity proportionately to the degree of nitration on tyrosine residues. Moreover, cell lysates prepared from MCF-10A cells treated with SIN-1 or DETA NONOate also showed much lower 4-methoxyestradiol-sulfating activities, compared with those determined with cell lysate prepared from control MCF-10A cells.