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Imidazopurinones are markers of physiological genomic damage linked to DNA instability and glyoxalase 1-associated tumour multidrug resistance

By Paul J. Thornalley, Sahar Waris, Thomas Fleming, Thomas Santarius, Sarah J. Larkin, Brigitte M. Winklhofer-Roob, Michael R. Stratton and Naila Rabbani


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

Topics: QP, RC0254
Publisher: Oxford University Press
Year: 2010
OAI identifier: oai:wrap.warwick.ac.uk:3384

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  3. (1996). Antitumour activity of S-pbromobenzylglutathione cyclopentyl diester in vitro and in vivo. Inhibition of glyoxalase I and induction of apoptosis. doi
  4. (2007). Apoptotic signaling in methylglyoxal-treated human osteoblasts involves oxidative stress, c-jun N-terminal kinase, caspase-3, and p21-activated kinase 2. doi
  5. (2009). Cancer craving for sugar: an opportunity for clinical exploitation. doi
  6. (2000). Deoxyguanosine adducts of 4-hydroxy-2-nonenal are endogenous DNA lesions in rodents and humans: detection and potential sources.
  7. (2004). Determination of glycated nucleobases in human urine by a new monoclonal antibody specific for N 2-carboxyethyl-20-deoxyguanosine. doi
  8. (1994). Development of a 32P-postlabelling technique for the analysis of 20-deoxyguanosine-30-monophosphate and DNA of methylglyoxal. doi
  9. (1998). DNA glycation leads to depurination by the loss of N2-carboxyethylguanine in vitro.
  10. (1996). Effect of methylglyoxal on human leukaemia 60 cell growth: modification of DNA, G1 growth arrest and induction of apoptosis. doi
  11. (2008). Efficient and accurate bypass of N 2-(1-carboxyethyl)-20-deoxyguanosine by DinB DNA polymerase in vitro and in vivo. doi
  12. (2004). Endogenous DNA damage in humans: a review of quantitative data. doi
  13. (2006). Evaluation of enzyme-linked immunosorbent assay and liquid chromatography-tandem mass spectrometry methodology for the analysis of 8-oxo-7,8-dihydro-20-deoxyguanosine in saliva and urine. doi
  14. (1997). Formation of guanosine adducts from L-ascorbic acid under oxidative conditions. doi
  15. (2000). Glyoxalase I is involved in resistance of human leukemia cells to antitumour agent-induced apoptosis.
  16. (2008). Glyoxalase-1 prevents mitochondrial protein modification and enhances lifespan in Caenorhabditis elegans. doi
  17. (2006). Hypoxia-inducible transcription factor-1alpha promotes hypoxia-induced A549 apoptosis via a mechanism that involves the glycolysis pathway. doi
  18. (1995). Identification of N 2(1-carboxyethyl)guanine (CEG) as a guanine advanced glycosylation endproduct. doi
  19. (2006). Increased dicarbonyl metabolism in endothelial cells in hyperglycemia induces anoikis and impairs angiogenesis by RGD and GFOGER motif modification. doi
  20. (2007). Influence on mitochondria and cytotoxicity of different antibiotics administered in high concentrations on primary human osteoblasts and cell lines. doi
  21. (1988). Inhibition of proliferation of human promyelocytic leukaemia HL60 cells by S-D-lactoylglutathione in vitro. doi
  22. (1995). Methylglyoxal induces HPRT mutation and DNA-adducts in human T-lymphocytes in vitro. doi
  23. (2006). N 2-carboxyethyl-2’-deoxyguanosine, a DNA glycation marker, in kidneys and aortas of diabetic and uremic patients. doi
  24. (1999). N2 (1-Carboxyethyl)deoxyguanosine, a nonenzymatic glycation adduct of DNA, induces single strand breaks and increases mutation frequences. doi
  25. (1969). On the reaction of guanine with glyoxal, pyruvaldehyde and ketoxal and the structure of the acylguanines. A new synthesis of N 2-alkylguanines. doi
  26. (2008). Preparation of nucleotide advanced glycation endproducts – imidazopurinone adducts formed by glycation of deoxyguanosine with glyoxal and methylglyoxal. doi
  27. (2010). Quantification of N2-carboxymethyl-2’-deoxyguanosine in calf thymus DNA and cultured human kidney epithelial cells by capillary high-performance liquid chromatography-tandem mass spectrometry coupled with stable isotope dilution method. doi
  28. (1973). Reactions of methylglyoxal with nucleic acids. doi
  29. (2002). Relative expression software tool (REST(C)) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. doi
  30. (2001). Selective activation of apoptosis program by S-p-bromobenzylglutathione cyclopentyl diester in glyoxalase I-overexpressing human lung cancer cells.
  31. (1984). Separation of lymphocytes, granulocytes, and monocytes from human blood using iodinated density gradient media. doi
  32. (2007). Stereospecific synthesis and characterization of oligodeoxyribonucleotides containing an doi
  33. (2006). Stimulation of suicidal erythrocyte death by methylglyoxal. doi
  34. (1993). The glyoxalase system in health and disease. doi
  35. (2002). The Maillard hypothesis on aging: time to focus on DNA. doi
  36. (2003). Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts. doi
  37. (2001). Vitamin A, vitamin E and carotenoid status and metabolism during ageing: functional and nutritional consequences
  38. (2004). Why do cancers have high aerobic glycolysis? Nature Revs. doi

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