Abordo E A, Minhas H S, Thornalley P J
Department of Biological Sciences, University of Essex, University of Essex, Colchester, UK.
Biochem Pharmacol. 1999 Aug 15;58(4):641-8. doi: 10.1016/s0006-2952(99)00132-x.
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.
乙二醛、甲基乙二醛（MG）和3-脱氧葡萄糖醛酮（3-DG）是由脂质过氧化、糖基化以及糖酵解中间产物降解形成的生理性α-氧代醛。它们在细胞内通过胞质谷胱甘肽依赖性乙二醛酶系统（仅针对乙二醛和MG）以及NADPH依赖性还原酶和NAD(P)+依赖性脱氢酶进行酶促解毒。在本研究中，研究了在过氧化氢和1-氯-2,4-二硝基苯（CDNB）的中等毒性浓度诱导的坏死性细胞死亡过程中，这些α-氧代醛在小鼠P388D1巨噬细胞内和细胞外浓度的变化。α-氧代醛浓度通过与1,2-二氨基-4,5-二甲氧基苯衍生化来测定。细胞内和细胞外乙二醛浓度仅有相对较小的增加，不过过氧化氢会使细胞外乙二醛浓度降低。然而，3-DG的胞质浓度以及MG的胞质和细胞外浓度显著增加。氨基胍抑制α-氧代醛的积累，并预防了过氧化氢和CDNB诱导的细胞毒性。乙二醛酶1原位活性降低可能是毒物处理细胞中乙二醛和MG积累的原因。这种影响对MG明显，但对乙二醛不明显，提示MG形成的代谢通量比乙二醛更大。毒物处理细胞中3-DG的积累可能是由于用于3-DG解毒的吡啶核苷酸辅因子可用性降低。α-氧代醛解毒受损具有细胞毒性，这可能导致与氧化应激和化学毒性中谷胱甘肽氧化和S结合相关的毒性，以及与糖尿病相关的慢性发病机制，糖尿病存在氧化应激且乙二醛、MG和3-DG的形成增加。
