Identifying the Tautomeric Form of a Deoxyguanosine-Estrogen Quinone Intermediate

Metabolites

Douglas E. Stack¹ 

[1] Department of Chemistry, University of Nebraska at Omaha, 6001 Dodge Street, Omaha, NE 68182, USA; E-Mail

关键词: estrogen o-quinones;    DNA damage;    carcinogenesis;    apurinic sites;    biomarkers;   

DOI  :  10.3390/metabo5030475

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.