Problematic detoxification of estrogen quinones by NAD(P)H-dependent quinone oxidoreductase and glutathione-S-transferase

Chem Res Toxicol. 2008 Jul;21(7):1324-9. doi: 10.1021/tx8000797. Epub 2008 Jun 28.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • DNA Adducts
  • DNA Damage
  • Estrogens, Catechol / pharmacokinetics*
  • Glutathione Transferase / metabolism*
  • Humans
  • Inactivation, Metabolic
  • NAD(P)H Dehydrogenase (Quinone) / metabolism*


  • DNA Adducts
  • Estrogens, Catechol
  • catechol estrogen 3,4-quinone
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • Glutathione Transferase