AN O-QUINONE FORM OF ESTROGEN PRODUCES FREE-RADICALS IN HUMAN BREAST-CANCER CELLS - CORRELATION WITH DNA-DAMAGE

The o-quinone forms of 2,3- and 3,4-catechol estrogens have been impli cated in the carcinogenicity of these hormones. The concomitant produc tion of reactive oxygen species during reduction of the o-quinone estr ogens has been inferred to play a mechanistic role in their mutagenic potential. Conclusive evidence documenting the production of hydrogen peroxide, the hydroxyl radical, and the estrone 3,4-semiquinone in est rone 3,4-quinone (3,4-EQ)-treated human breast cancer subcellular frac tions was demonstrated in the absence of exogenously added catalysts. Subcellular fractions of MCF-7 cells treated with 3,4-EQ and NADPH, in cluding nuclei, mitochondria, and microsomes, were shown to support si gnificant amounts of hydrogen peroxide production. Hydrogen peroxide p roduction in 3,4-EQ-treated cellular fractions and the chromosomal DNA damage induced in 3,4-EQ-treated MCF-7 cells were abolished by the ad dition of catalase. A significant and potentially physiologically rele vant spontaneous reduction of 3,4-EQ by NADPH resulting in hydrogen pe roxide production was demonstrated. The results unequivocally demonstr ate that free radicals are produced during the metabolism of estrone 3 ,4-quinone in human cells.