In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M1dG

Michael B. Otteneder, Charles G. Knutson, J. Scott Daniels, Muhammed Hashim, Brenda C. Crews, Rory P. Remmel, Hao Wang, Carmelo Rizzo, Lawrence J. Marnett

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

3-(2-Deoxy-β-D-erythro-pentofuranosyl)pyrimido[1,2-α] purin-10(3H)-one (M1dG) is a DNA adduct arising from the reaction of 2-deoxyguanosine with the lipid peroxidation product, malondialdehyde, or the DNA peroxidation product, base propenal. M1dG is mutagenic in bacteria and mammalian cells and is present in the genomic DNA of healthy human beings. It is also detectable, albeit at low levels, in the urine of healthy individuals, which may make it a useful biomarker of DNA damage linked to oxidative stress. We investigated the possibility that the low urinary levels of M1dG reflect metabolic conversion to derivatives. M1dG was rapidly removed from plasma (t1/2 = 10 min) after i.v. administration to rats. A single urinary metabolite was detected that was identified as 6-oxo-M1dG by MS, NMR spectroscopy, and independent chemical synthesis. 6-OxO-M1dG was generated in vitro by incubation of M1dG with rat liver cytosols, and studies with inhibitors suggested that xanthine oxidase and aldehyde oxidase are involved in the oxidative metabolism. M1dG also was metabolized by three separate human liver cytosol preparations, indicating 6-oxo-M1dG is a likely metabolite in humans. This represents a report of the oxidative metabolism of an endogenous DNA adduct and raises the possibility that other endogenous DNA adduces are metabolized by oxidative pathways. 6-Oxo-M1dG may be a useful biomarker of endogenous DNA damage associated with inflammation, oxidative stress, and certain types of cancer chemotherapy.

Original languageEnglish (US)
Pages (from-to)6665-6669
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number17
DOIs
StatePublished - Apr 25 2006

Keywords

  • DNA damage
  • Excretion
  • Inflammation
  • Metabolite
  • Oxidation

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