Estrogen exposure through early menarche, late menopause, and
hormone replacement therapy increases the risk factor for
hormone-dependent
cancers. Although the molecular mechanisms are not completely established, DNA damage by
quinone electrophilic reactive intermediates, derived from
estrogen oxidative metabolism, is strongly implicated. A current hypothesis has 4-hydroxyestrone-o-quinone (4-OQE) acting as the proximal
estrogen carcinogen, forming depurinating
DNA adducts via Michael addition. One aspect of this hypothesis posits a key role for
NAD(P)H-dependent
quinone oxidoreductase (NQO1) in the reduction of 4-OQE and protection against
estrogen carcinogenesis, despite two reports that 4-OQE is not a substrate for NQO1. 4-OQE is rapidly and efficiently trapped by GSH, allowing measurement of
NADPH-dependent reduction of 4-OQE in the presence and absence of NQO1. 4-OQE was observed to be a substrate for NQO1, but the acceleration of
NADPH-dependent reduction by NQO1 over the nonenzymic reaction is less than 10-fold and at more relevant nanomolar concentrations of substrate is less than 2-fold. An alternative detoxifying
enzyme,
glutathione-S-transferase, was observed to be a target for 4-OQE, rapidly undergoing covalent modification. These results indicate that a key role for NQO1 and GST in direct detoxification of 4-hydroxy-estrogen
quinones is problematic.