The elevated level of circulating estradiol increases the risk of breast tumor development. To gain further insight into mechanisms involved in their actions, we investigated the molecular mechanisms of 4-hydroxyestradiol (4-OHE2) to initiate and/or promote abnormal cell growth, and of alpha- or gamma-tocopherol to inhibit this process. MCF-10A, human breast epithelial cells were incubated with 0.1 microM 4-OHE2, either with or without 30 microM tocopherols for 96 h. 4-OHE2 caused the accumulation of intracellular ROS, while cellular GSH/GSSG ratio and MnSOD protein levels were decreased, indicating that there was an oxidative burden. 4-OHE2 treatment also changed the levels of DNA repair proteins, BRCA1 and PARP-1. gamma-Tocopherol suppressed the 4-OHE2-induced increases in ROS, GSH/GSSG ratio, and MnSOD protein expression, while alpha-tocopherol up-regulated BRCA1 and PARP-1 protein expression. In conclusion, 4-OHE2 increases oxidative stress reducing the level of proteins related to DNA repair. Tocopherols suppressed oxidative stress by scavenging ROS or up-regulating DNA repair elements.
alpha-Tocopherol ; Breast ; Breast Neoplasms ; DNA Damage ; DNA Repair ; Epithelial Cells ; Estradiol ; Estrogens, Catechol ; gamma-Tocopherol ; Humans ; Oxidative Stress ; Proteins ; Tocopherols

PURPOSE: Many gene polymorphisms are associated with coronary artery abnormalities in Kawasaki disease. Catechol-O-methyltransfe rase (COMT) plays an important role in the metabolism of catecholamines, catechol estrogen, and catechol drugs. Polymorphisms of the COMT gene are reported to be associated with myocardial infarction and coronary artery abnormalities. The aim of this study was to evaluate the relationship between COMT gene polymorphisms and coronary artery abnormalities in Kawasaki disease patients. METHODS: One hundred and one Korean children with Kawasaki disease and 306 healthy Korean control subjects were enrolled in this study. The polymorphisms of the COMT gene were analyzed by direct sequencing. RESULTS: There were no differences in the genotype and allelic frequency of the rs4680 and rs769224 polymorphic sites between Kawasaki disease and control subjects. Further, no significant difference was found in the rs4680 polymorphism between patients with coronary artery abnormalities and patients without coronary artery abnormalities (codominant P=0.32, dominant P=0.74, recessive P=0.13). However, the distribution of the rs769224 polymorphism was significantly different between patie nts with coronary artery abnormalities and patients without coronary artery abnormalities (codominant P=0.0077, dominant P=0.0021, recessive P=0.16). CONCLUSION: Our results indicate that the polymorphisms of the rs769224 gene might be related to the development of coronary artery abnormalities in Kawasaki disease.
Catechol O-Methyltransferase ; Catecholamines ; Catechols ; Child ; Coronary Artery Disease ; Coronary Vessels ; Estrogens ; Genotype ; Humans ; Mucocutaneous Lymph Node Syndrome ; Myocardial Infarction ; Polymorphism, Genetic

Animals ; Benzhydryl Compounds ; toxicity ; Biomarkers ; analysis ; blood ; Breast Neoplasms ; chemically induced ; Drug Synergism ; Endocrine Disruptors ; toxicity ; Estrone ; metabolism ; Genistein ; adverse effects ; Hydroxyestrones ; analysis ; Male ; Microsomes, Liver ; drug effects ; metabolism ; Oxidation-Reduction ; Phenols ; toxicity ; Rats, Wistar