Mechanisms of Metabolic Activation and Inactivation of Catecholestrogens: A Basis of Genotoxicity

Abstract

Abstract A mechanism of estrogen-induced carcinogenesis is examined which focuses on metabolic activation of estrogens and induction of cell damage prior to completion of the carcinogenic process by receptor-mediated cell transformation and tumor growth. Catecholestrogen metabolites or diethylstilbestrol may be metabolized to their quinones, which, in turn, may be reduced to the parent hydroquinone forms. This metabolic redox cycling is a source of potentially mutagenic free radicals. In this review, three types of estrogen-induced DNA damage are discussed: (i) covalent binding of estrogen quinone intermediates to DNA; (ii) free radical-mediated DNA damage such as single strand breaks and 8-hydroxylation of guanine bases of DNA; and (iii) DNA adducts formed by lipid hydroperoxides or their decomposition products. Lipid hydroperoxides are proposed to play a key role in estrogen-induced carcinogenesis. As oxidants, they are consumed by supporting redox cycling. At the same time, they are formed as a result of redox cycling of estrogens. In the future, the biological consequences of this DNA damage needs to be examined and its role in estrogen-induced carcinogenesis.