Accumulation of α-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 P388D(1) 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-treat ed 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. (C) 1999 Elsevier Science Inc.