title: 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.
abstract: 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.
authors.affiliation: A. B. Hancock Jr. Memorial Laboratory for Cancer Research, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Knutson
authors.forename: Paul L
authors.initials: PL
authors.lastname: Skipper
authors.forename: Rosa G
authors.initials: RG
authors.lastname: Liberman
authors.forename: Steven R
authors.initials: SR
authors.lastname: Tannenbaum
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
mesh_terms: D000818:Animals; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D008297:Male; D013058:Mass Spectrometry; D011684:Purine Nucleosides / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014556:Urine / Q000737:chemistry
chemical_list: C491625:3-(2'-deoxy-beta-D-erythro-pentofuranosyl)pyrimido(1,2-alpha)purin-10(3H)-one; D018736:DNA Adducts; D011684:Purine Nucleosides