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. 2009 May;22(5):913-7.
doi: 10.1021/tx900002g.

Inherent stereospecificity in the reaction of aflatoxin B(1) 8,9-epoxide with deoxyguanosine and efficiency of DNA catalysis

Kyle L Brown  1 , Urban Bren, Michael P Stone, F Peter Guengerich
Affiliations

Inherent stereospecificity in the reaction of aflatoxin B(1) 8,9-epoxide with deoxyguanosine and efficiency of DNA catalysis

Kyle L Brown et al. Chem Res Toxicol. 2009 May.

Abstract

Kinetic analysis of guanine alkylation by aflatoxin B(1) exo-8,9-epoxide, the reactive form of the hepatocarcinogen aflatoxin B(1), shows the reaction to be >2000 times more efficient in DNA than in aqueous solution, that is, with free 2'-deoxyguanosine. Thermodynamic analysis reveals AFB(1) exo-8,9-epoxide intercalation as the predominant source of the observed DNA catalytic effect. However, the known exo > endo epoxide stereospecificity of the DNA alkylation is observed even with free deoxyguanosine (ratio >20:1 determined by LC-MS and NMR measurements), as predicted by theoretical calculations [ Bren , U. , et al. ( 2007 ) Chem. Res. Toxciol. 20 , 1134 - 1140 ].

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Figures

Figure 1
Figure 1
Formation of AFB1-dGuo adduct as a function of dGuo concentration. Error-bars depict experimental adduct yields and line represents kinetic model of Equation 1 using a knon value of 12.6 M−1 s−1.
Figure 2
Figure 2
1H-NMR spectrum of isolated AFB1-Gua adduct. The shift assignments (19) and expected shift values of an endo product are shown. Expansions are in the boxes.
Figure 3
Figure 3
Schematic free-energy profiles for guanine alkylation by AFB1 exo-8,9-epoxide in DNA (red) and in aqueous solution (green). For details and definition of symbols see Equations 3 to 5.
Scheme 1
Scheme 1
Competing reactions of AFB1 exo-8,9-epoxide with dGuo and H2O.
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