Synergistic Induction of DNA Strand Breakage by Catechol-Estrogen and Nitric Oxide: Implications for Hormonal Carcinogenesis

摘要: Estrogen is a known risk factor for human breast cancer, although the mechanism by which estrogens induce cancer remains unestablished. We have demonstrated that DNA strand breakage induced synergistically when pBR322 plasmid incubated in presence of both nitric oxide (NO)-releasing compound (diethylamine NONOate, etc.) and catechol-estrogen (2- or 4-hydroxyestradiol -hydroxyestrone). Either NO-releasing alone much fewer breaks. Estradiol, estrone, O-methylated catechol-estrogens, diethylstilbestrol did not exert such damaging effects. Strand NO plus 2- was inhibited carboxy-PTIO (an NO-trapping agent) and, to lesser extent, superoxide dismutase. Antioxidants (e.g., N-acetylcysteine, ascorbate), but HO. scavengers, exhibited inhibitory A possible this would be: (1) mediates conversion catechol-estrogens quinones, (2) quinone/hydroquinone redox system produces O2.-, (3) O2.- reacts with form peroxynitrite, causes Our results imply interaction NO, be formed uterus, leads production potent oxidant(s), could cause damage cells DNA, thus playing an important role hormonal carcinogenesis.