title: Imidazopurinones are markers of physiological genomic damage linked to DNA instability and glyoxalase 1-associated tumour multidrug resistance.
abstract: Glyoxal and methylglyoxal are reactive dicarbonyl metabolites formed and metabolized in physiological systems. Increased exposure to these dicarbonyls is linked to mutagenesis and cytotoxicity and enhanced dicarbonyl metabolism by overexpression of glyoxalase 1 is linked to tumour multidrug resistance in cancer chemotherapy. We report herein that glycation of DNA by glyoxal and methylglyoxal produces a quantitatively important class of nucleotide adduct in physiological systems-imidazopurinones. The adduct derived from methylglyoxal-3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6/7-methylimidazo-[2,3-b]purine-9(8)one isomers-was the major quantitative adduct detected in mononuclear leukocytes in vivo and tumour cell lines in vitro. It was linked to frequency of DNA strand breaks and increased markedly during apoptosis induced by a cell permeable glyoxalase 1 inhibitor. Unexpectedly, the DNA content of methylglyoxal-derived imidazopurinone and oxidative marker 7,8-dihydro-8-oxo-2'-deoxyguanosine were increased moderately in glyoxalase 1-linked multidrug resistant tumour cell lines. Together these findings suggest that imidazopurinones are a major type of endogenous DNA damage and glyoxalase 1 overexpression in tumour cells strives to counter increased imidazopurinone formation in tumour cells likely linked to their high glycolytic activity.
authors.affiliation: Warwick Medical School, Clinical Sciences Research Institute, University of Warwick, University Hospital, Coventry CV2 2DX, UK. p.j.thornalley@warwick.ac.uk
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Thornalley
authors.forename: Sahar
authors.initials: S
authors.lastname: Waris
authors.forename: Thomas
authors.initials: T
authors.lastname: Fleming
authors.forename: Thomas
authors.initials: T
authors.lastname: Santarius
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Larkin
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Winklhofer-Roob
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Naila
authors.initials: N
authors.lastname: Rabbani
mesh_terms: D015415:Biomarkers / Q000032:analysis / Q000737:chemistry; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D018736:DNA Adducts / Q000097:blood / Q000737:chemistry / Q000652:urine; D053960:DNA Breaks; D004273:DNA, Neoplasm / Q000737:chemistry*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006037:Glyoxal / Q000737:chemistry; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000378:metabolism*; D009705:Nucleosides / Q000097:blood / Q000652:urine; D011688:Purinones / Q000032:analysis* / Q000737:chemistry; D011765:Pyruvaldehyde / Q000737:chemistry; D053719:Tandem Mass Spectrometry
chemical_list: D015415:Biomarkers; D018736:DNA Adducts; D004273:DNA, Neoplasm; D009705:Nucleosides; D011688:Purinones; D006037:Glyoxal; D011765:Pyruvaldehyde; D007791:Lactoylglutathione Lyase