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 (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 (t(1/2) = 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 adducts 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.
Otteneder
Michael B
MB
Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
Knutson
Charles G
CG
Daniels
J Scott
JS
Hashim
Muhammed
M
Crews
Brenda C
BC
Remmel
Rory P
RP
Wang
Hao
H
Rizzo
Carmelo
C
Marnett
Lawrence J
LJ
D000818:Animals; D003600:Cytosol / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D007700:Kinetics; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011684:Purine Nucleosides / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
C491625:3-(2'-deoxy-beta-D-erythro-pentofuranosyl)pyrimido(1,2-alpha)purin-10(3H)-one; D018736:DNA Adducts; D011684:Purine Nucleosides