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Analysis of the reaction between 2'-deoxyadenosine and 4-oxo-2-nonenal by liquid chromatography/mass spectrometry revealed the presence of three major products (adducts A(1), A(2), and B). Adducts A(1) and A(2) were isomeric; they interconverted at room temperature, and they each readily dehydrated to form adduct B. The mass spectral characteristics of adduct B obtained by collision-induced dissociation coupled with multiple tandem mass spectrometry were consistent with those expected for a substituted etheno adduct. The structure of adduct B was shown by NMR spectroscopy to be consistent with the substituted etheno-2'-deoxyadenosine adduct 1' '-[3-(2'-deoxy-beta-D-erythropentafuranosyl)-3H-imidazo[2, 1-i]purin-7-yl]heptane-2' '-one. Unequivocal proof of structure came from the reaction of adducts A(1) and A(2) (precursors of adduct B) with sodium borohydride. Adducts A(1) and A(2) each formed the same reduction product, which contained eight additional hydrogen atoms. The mass spectral characteristics of this reduction product established that the exocyclic amino group (N(6)) of 2'-deoxyadenosine was attached to C-1 of the 4-oxo-2-nonenal. The reaction of 4-oxo-2-nonenal with calf thymus DNA was also shown to result in the formation of substituted ethano adducts A(1) and A(2) and substituted etheno adduct B. Adduct B was formed in amounts almost 2 orders of magnitude greater than those of adducts A(1) and A(2). This was in keeping with the observed stability of the adducts. The study presented here has provided additional evidence which shows that 4-oxo-2-nonenal reacts efficiently with DNA to form substituted etheno adducts.

This article is available online at http://dmd.aspetjournals.org ABSTRACT:A pharmacokinetics and metabolism study was conducted in eight healthy human volunteers. After oral administration of EP and its metabolites did not preferentially partition into the red blood cells and blood concentrations of total radioactivity were lower than plasma concentrations. Approximately 66.6% and 32.0% of the radioactive dose were excreted in urine and feces, respectively. The majority of urinary and fecal radioactivity was due to metabolites, indicating extensive metabolism of EP. The major metabolic pathways were 6␤-and/or 21-hydroxylation and 3-keto reduction. There was no evidence for any alteration of the 9,11-epoxide ring or the methyl ester. As a percentage of dose, the primary metabolic products excreted in urine and feces included 6␤-hydroxy-EP (6␤-OHEP) (32.0%), 6␤,21-OHEP (20.5%), 21-OHEP (7.89%), and 2␣,3␤,21-OHEP (5.96%). The amounts of the other metabolites excreted were less than 5% each.