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

3-(2-Deoxy-beta-D-erythro-pentofuranosyl)pyrimido[1,2-alpha]purin-10(3H)-one (M(1)dG) is a DNA adduct arising from the reaction of 2-deoxy-guanosine 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 (t(1/2) = 10 min) after i.v. administration to rats. A single urinary metabolite was detected that was identified as 6-oxo-M(1)dG by MS, NMR spectroscopy, and independent chemical synthesis. 6-Oxo-M(1)dG was generated in vitro by incubation of M(1)dG 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-M(1)dG 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 adducts are metabolized by oxidative pathways. 6-Oxo-M(1)dG may be a useful biomarker of endogenous DNA damage associated with inflammation, oxidative stress, and certain types of cancer chemotherapy.