Samuni A.MERIC YAO-YU CHUANGKrishna M.CStein WDeGraff WRusso AMitchell J.B.2023-06-092023-06-092003278424https://www.scopus.com/inward/record.uri?eid=2-s2.0-0037627447&doi=10.1073%2fpnas.0930078100&partnerID=40&md5=16fb925590a50454b17f831dc3839a47https://scholars.lib.ntu.edu.tw/handle/123456789/632532Modulation of the cytotoxicity and mutagenicity of 4-hydroxyestradiol (4-OHE2), 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-OHE2 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-OHE2 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.1,4 dihydroxytetramethylpiperidine; 4 hydroxyestradiol; antioxidant; ascorbic acid; catechol; cysteine; estrogen; glutathione; oxygen; piperidine derivative; semiquinone; tempol; unclassified drug; article; breast cancer; cell culture; cell survival; chemoprophylaxis; controlled study; cytotoxicity; electron spin resonance; human; human cell; mutagenesis; oxygen concentration; priority journal; Antioxidants; Cell Line; Electron Spin Resonance Spectroscopy; Estrogens, Catechol; Free Radicals; Humans; Mutagenesis; Quinonesjournal article10.1073/pnas.0930078100127027792-s2.0-0037627447