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Metabolites 2015, 5(3), 475-488; doi:10.3390/metabo5030475

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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Abstract

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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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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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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