Monitoring in vivo metabolism and elimination of the endogenous DNA adduct, M1dG {3-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrimido[1,2-alpha]purin-10(3H)-one}, by accelerator mass spectrometry.

Our laboratory is investigating the in vitro and in vivo metabolic processing of endogenously formed DNA adducts as a means of evaluating candidate urinary biomarkers. In particular, we have focused our studies on the metabolism and disposition of the peroxidation-derived pyrimidopurinone deoxyguanosine (dG) adduct, 3-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrimido[1,2-R]purin-10(3H)-one (M1dG), and its principal metabolite, 6-oxo-M1dG. We now report the metabolic processing of M1dG at concentrations 4-8 orders of magnitude lower in concentration than previously analyzed, by the use of accelerator mass spectrometry analysis. Administration of 2.0 nCi/kg [14C]M1dG resulted in 49% of the 14C recovered in urine, whereas 51% was recovered in feces. In urine samples, approximately 40% of the 14C corresponded to the metabolite, 6-oxo-M1dG. Following iv administration of 0.5 and 54 pCi/kg [14C]M1dG, approximately 25% of the urinary recovery corresponded to the metabolite, 6-oxo-M1dG. Thus, upon administration of trace amounts of M1dG, a significant percentage of 6-oxo-M1dG was produced, suggesting that 6-oxo-M1dG maybe a useful urinary marker of exposure to endogenous oxidative damage.