Chandrasena, R. Esala P. and Edirisinghe, Praneeth D. and Bolton, Judy L. and Thatcher, Gregory R. J. (2008) Problematic detoxitication of estrogen quinones by NAD(P)H-dependent quinone oxidoreductase and glutathione-S-transferase. CHEMICAL RESEARCH IN TOXICOLOGY, 21 (7). pp. 1324-1329.
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Official URL: http://pubs.acs.org/doi/abs/10.1021/tx8000797
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 quinione 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.
|Subjects:||Biomedical Science > Nanomedicine|
|Deposited On:||21 Jan 2009 11:56|
|Last Modified:||21 Jan 2009 11:56|
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