Estrogen Metabolism: Does the Formation of Estrogen Quinone Provide a Potential Pathway to Breast Carcinogenesis?
Estrogen has long been implicated in the initiation of carcinogenesis in estrogen-sensitive tissues through receptor-mediated events (Girder and Brotherick, 2000). However recent studies indicate that estrogens may cause DNA damage directly and independent of receptor-mediated mechanisms through the oxidation products of estrogen metabolism. The major pathway for estrogen metabolism proceeds by two steps: First the aromatic hydroxylation of the primary estrogens to form 2- and 4-hydroxycatechol estrogens. Under normal conditions these catechols rapidly undergo O-methylation, catalyzed by catechol-O-methyltransferase (COMT). The evidence for the rapid O-methylation is several fold. While virtually all catechols are substrates for COMT the highest affinities for the enzyme are exhibited by the catechol estrogens (Ball and Knuppen, 1985). Further the O-methylated products are the major urinary estrogen metabolites. Importantly, the efficiency of the O-methylation pathway is reflected in the extremely short half-life of catechol estrogens (Lipsett et. al. 1983).
KeywordsCOMT Gene Estrogen Metabolism Catechol Estrogen Japanese Diet Apurinic Site
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