title: Problematic detoxification of estrogen quinones by NAD(P)H-dependent quinone oxidoreductase and glutathione-S-transferase.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA.
authors.forename: R Esala P
authors.initials: RE
authors.lastname: Chandrasena
authors.forename: Praneeth D
authors.initials: PD
authors.lastname: Edirisinghe
authors.forename: Judy L
authors.initials: JL
authors.lastname: Bolton
authors.forename: Gregory R J
authors.initials: GR
authors.lastname: Thatcher
mesh_terms: D018736:DNA Adducts; D004249:DNA Damage; D002393:Estrogens, Catechol / Q000493:pharmacokinetics*; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*
chemical_list: D018736:DNA Adducts; D002393:Estrogens, Catechol; C116356:catechol estrogen 3,4-quinone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D005982:Glutathione Transferase