Accumulation of alpha-oxoaldehydes during oxidative stress: a role in cytotoxicity.
Glyoxal, methylglyoxal (MG), and 3-deoxyglucosone (3-DG) are physiological alpha-oxoaldehydes formed by lipid peroxidation, glycation, and degradation of glycolytic intermediates. They are enzymatically detoxified in cells by the cytosolic glutathione-dependent glyoxalase system (glyoxal and MG only) and by NADPH-dependent reductase and NAD(P)+-dependent dehydrogenase. In this study, the changes in the cellular and extracellular concentrations of these alpha-oxoaldehydes were investigated in murine P388D1 macrophages during necrotic cell death induced by median toxic concentrations of hydrogen peroxide and 1-chloro-2,4-dinitrobenzene (CDNB). Alpha-oxoaldehyde concentrations were determined by derivatization with 1,2-diamino-4,5-dimethoxybenzene. There were relatively small increases in cellular and extracellular glyoxal concentration, except that extracellular glyoxal was decreased with hydrogen peroxide. The cytosolic concentration of 3-DG and the cytosolic and extracellular concentrations of MG, however, increased markedly. Aminoguanidine inhibited alpha-oxoaldehyde accumulation and prevented cytotoxicity induced by hydrogen peroxide and CDNB. The accumulation of glyoxal and MG in toxicant-treated cells was a likely consequence of decreased in situ activity of glyoxalase 1. The effect was marked for MG but not for glyoxal, suggestive of a greater metabolic flux of MG formation than of glyoxal. The accumulation of 3-DG in toxicant-treated cells was probably due to the decreased availability of pyridine nucleotide cofactors for the detoxification of 3-DG. Impairment of alpha-oxoaldehyde detoxification is cytotoxic, and this may contribute to toxicity associated with GSH oxidation and S conjugation in oxidative stress and chemical toxicity, and to chronic pathogenesis associated with diabetes mellitus where there is oxidative stress and the formation of glyoxal, MG, and 3-DG is increased.
Abordo
E A
EA
Department of Biological Sciences, University of Essex, University of Essex, Colchester, UK.
Minhas
H S
HS
Thornalley
P J
PJ
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003847:Deoxyglucose / Q000031:analogs & derivatives* / Q000378:metabolism; D004137:Dinitrochlorobenzene / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006037:Glyoxal / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009336:Necrosis; D019335:Nitroarginine / Q000494:pharmacology; D018384:Oxidative Stress; D011765:Pyruvaldehyde / Q000378:metabolism*
D004137:Dinitrochlorobenzene; D006146:Guanidines; D019335:Nitroarginine; D006037:Glyoxal; D011765:Pyruvaldehyde; D003847:Deoxyglucose; D006861:Hydrogen Peroxide; C016350:3-deoxyglucosone; D005978:Glutathione; C004479:pimagedine