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Metabolites 2015, 5(3), 475-488;

Identifying the Tautomeric Form of a Deoxyguanosine-Estrogen Quinone Intermediate

Department of Chemistry, University of Nebraska at Omaha, 6001 Dodge Street, Omaha, NE 68182, USA
Academic Editor: Peter Meikle
Received: 11 June 2015 / Revised: 3 September 2015 / Accepted: 6 September 2015 / Published: 10 September 2015
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Mechanistic insights into the reaction of an estrogen o-quinone with deoxyguanosine has been further investigated using high level density functional calculations in addition to the use of 4-hyroxycatecholestrone (4-OHE1) regioselectivity labeled with deuterium at the C1-position. Calculations using the M06-2X functional with large basis sets indicate the tautomeric form of an estrogen-DNA adduct present when glycosidic bonds cleavage occurs is comprised of an aromatic A ring structure. This tautomeric form was further verified by use of deuterium labelling of the catechol precursor use to form the estrogen o-quinone. Regioselective deuterium labelling at the C1-position of the estrogen A ring allows discrimination between two tautomeric forms of a reaction intermediate either of which could be present during glycosidic bond cleavage. HPLC-MS analysis indicates a reactive intermediate with a m/z of 552.22 consistent with a tautomeric form containing no deuterium. This intermediate is consistent with a reaction mechanism that involves: (1) proton assisted Michael addition; (2) re-aromatization of the estrogen A ring; and (3) glycosidic bond cleavage to form the known estrogen-DNA adduct, 4-OHE1-1-N7Gua. View Full-Text
Keywords: estrogen o-quinones; DNA damage; carcinogenesis; apurinic sites; biomarkers estrogen o-quinones; DNA damage; carcinogenesis; apurinic sites; biomarkers

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Stack, D.E. Identifying the Tautomeric Form of a Deoxyguanosine-Estrogen Quinone Intermediate. Metabolites 2015, 5, 475-488.

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