title: Oxidative DNA damage and mammary cell proliferation by alcohol-derived salsolinol.
abstract: Drinking alcohol is a risk factor for breast cancer. Salsolinol (SAL) is endogenously formed by a condensation reaction of dopamine with acetaldehyde, a major ethanol metabolite, and SAL is detected in blood and urine after alcohol intake. We investigated the possibility that SAL can participate in tumor initiation and promotion by causing DNA damage and cell proliferation, leading to alcohol-associated mammary carcinogenesis. SAL caused oxidative DNA damage including 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), in the presence of transition metal ions, such as Cu(II) and Fe(III)EDTA. Inhibitory effects of scavengers on SAL-induced DNA damage and the electron spin resonance study indicated the involvement of H₂O₂, which is generated via the SAL radical. Experiments on scavengers and site specificity of DNA damage suggested ·OH generation via a Fenton reaction and copper-peroxide complexes in the presence of Fe(III)EDTA and Cu(II), respectively. SAL significantly increased 8-oxodG formation in normal mammary epithelial MCF-10A cells. In addition, SAL induced cell proliferation in estrogen receptor (ER)-negative MCF-10A cells, and the proliferation was inhibited by an antioxidant N-acetylcysteine and an epidermal growth factor receptor (EGFR) inhibitor AG1478, suggesting that reactive oxygen species may participate in the proliferation of MCF-10A cells via EGFR activation. Furthermore, SAL induced proliferation in estrogen-sensitive breast cancer MCF-7 cells, and a surface plasmon resonance sensor revealed that SAL significantly increased the binding activity of ERα to the estrogen response element but not ERβ. In conclusion, SAL-induced DNA damage and cell proliferation may play a role in tumor initiation and promotion of multistage mammary carcinogenesis in relation to drinking alcohol.
authors.affiliation: Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine , Tsu, Mie 514-8507, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Murata
authors.forename: Kaoru
authors.initials: K
authors.lastname: Midorikawa
authors.forename: Shosuke
authors.initials: S
authors.lastname: Kawanishi
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000111:Acetylcysteine / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry; D004249:DNA Damage / Q000187:drug effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000737:chemistry; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism; D000431:Ethanol / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism; D007501:Iron / Q000737:chemistry; D007546:Isoquinolines / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D061986:MCF-7 Cells; D042361:Mammary Glands, Human / Q000166:cytology; D018384:Oxidative Stress / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D028561:Transition Elements / Q000737:chemistry; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D056831:Coordination Complexes; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C045076:Fenton's reagent; D007546:Isoquinolines; D011799:Quinazolines; D028561:Transition Elements; D020032:Tyrphostins; C101044:RTKI cpd; D000431:Ethanol; D000080242:8-Hydroxy-2'-Deoxyguanosine; C036617:salsolinol; D006861:Hydrogen Peroxide; D007501:Iron; D066246:ErbB Receptors; D003849:Deoxyguanosine; D000111:Acetylcysteine