Glycation of
nucleotides in
DNA forms AGEs (
advanced glycation end-products).
Nucleotide AGEs are: the imidazopurinone derivative dG-G [3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxyimidazo[2,3-b]purin-9(8)one], CMdG ( N (2)-carboxymethyldeoxyguanosine) and gdC (5-glycolyldeoxycytidine) derived from
glyoxal, dG-MG [6,7-dihydro-6,7-dihydroxy-6-methylimidazo-[2,3-b]
purine-9(8)one], dG-MG(2) [ N (2),7-bis-(1-hydroxy-2-oxopropyl)
deoxyguanosine] and CEdG [ N (2)-(1-carboxyethyl)
deoxyguanosine] derived from
methylglyoxal, and dG-3DG [ N (2)-(1-oxo-2,4,5,6-tetrahydroxyhexyl)
deoxyguanosine] derived from
3-deoxyglucosone and others.
Glyoxal and
methylglyoxal induce multi-base deletions, and base-pair substitutions - mostly occurring at G:C sites with G:C-->C:G and G:C-->T:A transversions. Suppression of
nucleotide glycation by
glyoxalase I and
aldehyde reductases and
dehydrogenases, and base excision repair, protects and recovers
DNA from damaging glycation. The effects of
DNA glycation may be most marked in diabetes and uraemia. Mutations arising from
DNA glycation may explain the link of non-
dietary carbohydrate intake to incidence of
colorectal cancer. Overexpression of
glyoxalase I was found in
drug-resistant tumour cells and may be an example of an undesirable effect of the enzymatic protection against
DNA glycation. Experimental overexpression of
glyoxalase I conferred resistance to
drug-induced apoptosis.
Glyoxalase I-mediated drug resistance was found in human leukaemia and lung
carcinoma cells.
Methylglyoxal-mediated glycation of
DNA may contribute to the cytotoxicity of some antitumour agents as a consequence of depletion of
NAD(+) by
poly(ADP-ribose) polymerase, marked increases in triosephosphate concentration and increased formation of
methylglyoxal. S - p -Bromobenzylglutathione cyclopentyl diester is a cell-permeable
glyoxalase I inhibitor. It countered drug resistance and was a potent antitumour agent against lung and prostate
carcinoma.
Glyoxalase I overexpression was also found in invasive
ovarian cancer and
breast cancer.