Semiquinone radical intermediate in catecholic estrogen-mediated cytotoxicity and mutagenesis: chemoprevention strategies with antioxidants.
Modulation of the cytotoxicity and mutagenicity of 4-hydroxyestradiol (4-OHE(2)), an oxidative metabolite of estrogen, by antioxidants was assessed in human MCF7 cells and TK-6 lymphoblast cells. The cytotoxicity of the catecholic estrogens was potentiated by depletion of intracellular glutathione and was independent of oxygen concentration. Agents such as the nitroxide Tempol can facilitate the oxidation of the semiquinone to the Q and enhanced 4-OHE(2) cytotoxicity. Conversely, reducing agents such as ascorbate, cysteine, and 1,4-dihydroxytetramethylpiperidine (THP) protected against cytotoxicity and decreased mutation induction, presumably by reducing the semiquinone to the hydroquinone. Our results support the proposition that oxidation of the semiquinone to the corresponding Q is crucial in eliciting the deleterious effects of catecholic estrogens. Furthermore, because the deleterious effects of 4-OHE(2) were abrogated by dietary and synthetic antioxidants, our results would support the chemopreventive use of diets rich in reducing substances (vitamins and added synthetic antioxidants) as a means of decreasing the risks associated with estrogen exposure and developing of breast cancer.
Samuni
Ayelet M
AM
Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room B3-B69, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Chuang
Eric Y
EY
Krishna
Murali C
MC
Stein
William
W
DeGraff
William
W
Russo
Angelo
A
Mitchell
James B
JB
D000975:Antioxidants / Q000378:metabolism*; D002460:Cell Line; D004578:Electron Spin Resonance Spectroscopy; D002393:Estrogens, Catechol / Q000378:metabolism*; D005609:Free Radicals; D006801:Humans; D016296:Mutagenesis; D011809:Quinones / Q000378:metabolism*
D000975:Antioxidants; D002393:Estrogens, Catechol; D005609:Free Radicals; D011809:Quinones