Accumulation of alpha-oxoaldehydes during oxidative stress: a role in cytotoxicity

Biochem Pharmacol. 1999 Aug 15;58(4):641-8. doi: 10.1016/s0006-2952(99)00132-x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Survival / drug effects
  • Deoxyglucose / analogs & derivatives*
  • Deoxyglucose / metabolism
  • Dinitrochlorobenzene / pharmacology
  • Glutathione / metabolism
  • Glyoxal / metabolism*
  • Guanidines / pharmacology
  • Hydrogen Peroxide / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mice
  • Necrosis
  • Nitroarginine / pharmacology
  • Oxidative Stress*
  • Pyruvaldehyde / metabolism*

Substances

  • Dinitrochlorobenzene
  • Guanidines
  • Nitroarginine
  • Glyoxal
  • Pyruvaldehyde
  • Deoxyglucose
  • Hydrogen Peroxide
  • 3-deoxyglucosone
  • Glutathione
  • pimagedine