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PubMed1996

Glucose formation from methylglyoxal in hepatocytes from streptozotocin-induced diabetic mice: the effect of insulin.

Acetol and methylglyoxal are intermediates of the intrahepatic metabolism of acetone leading to pyruvate formation. In hepatocytes prepared from fasted streptozotocin-induced diabetic mice, net glucose production could be measured from methylglyoxal but not from acetone or acetol. Insulin increased glucose formation from methylglyoxal in a concentration-dependent manner, whereas it was ineffective when pyruvate was used as substrate. Drug oxidation, as evidenced by p-aminophenol formation from aniline, was enhanced by methylglyoxal, and insulin proved to be stimulatory in this case as well. It is concluded that insulin might be involved in the regulation of glucose formation from methylglyoxal, but its mode of action is not yet clear.

Acetone↗
PubMed1993

Has reactive oxygen a role in methylglyoxal toxicity? A study on cultured rat hepatocytes.

The toxicity of methylglyoxal and its ability to generate reactive oxygen species were investigated in cultured rat hepatocytes. Under aerobic and anaerobic conditions methylglyoxal increased lactate dehydrogenase (LDH) release and trypan blue uptake in a concentration dependent manner. Those concentrations of methylglyoxal causing cell injury (1 mM <) also caused the release of reactive oxygen species as indicated by peroxidase-catalyzed luminol chemiluminescence. Release of reactive oxygen was detectable only under aerobic conditions, and only became significant when a large portion of the cells had already lost their viability. It is concluded that methylglyoxal injuries cultured rat hepatocytes and induces the generation of reactive oxygen species. The reactive oxygen species, however, are essentially not involved in methylglyoxal hepatotoxicity but are released by already severely injured cells.

Aerobiosis↗
PubMed1981

Studies on the inactivation of glyceraldehyde-3-phosphate dehydrogenase by methylglyoxal.

Glyceraldehyde-3-P dehydrogenase (E.C. 1.2.1.12) from rabbit muscle is rapidly inactivated by methylglyoxal following pseudo first-order kinetics. Substrate, as well as inorganic phosphate, affords protection, whereas NAD+ is ineffective. The arginine residue implicated in the reaction is probably the anion binding site of the phosphate group of the substrate.

Aldehydes↗
PubMedDate not supplied

Evidence that high-dose L-arginine may be inappropriate for use by diabetic patients as a prophylactic blocker of methylglyoxal glycation.

Previous reports have suggested that high-dose L-arginine could be used in diabetic patients as a prophylactic blocker for the initial glycation reaction of proteins by methylglyoxal (MG), a reactive dicarbonyl compound of glucose metabolism. Here, we present several lines of evidence to substantiate that this prophylactic intervention may be inappropriate and should be used with care. First, we demonstrated that when various concentrations of L-arginine (2.0-8.0 mM) were added to a fixed concentration of MG (1.56 microM) in a buffered lucigenin solution, dose-dependent generation of superoxide anion (O(-)(2))-mediated ultraweak chemiluminescence (uwCL) occurs. The suppression of uwCL generation by exogenously added superoxide dismutase further substantiated that the interaction between MG and L-arginine generated O(-)(2). This phenomenon can also be demonstrated in a serum-based system. Furthermore, when a fixed concentration of L-arginine (8.0 mM) was added exogenously to a group of sera obtained from either diabetic patients (n = 10) or their matched nondiabetic controls (n = 10), a marked discrepancy in the generation of O(-)(2)-mediated uwCL could be demonstrated (12,534 +/- 3,147 vs. 950 +/- 350 counts; p < 0.001). Taken together, this evidence demonstrates that the appropriateness of using high-dose L-arginine for prophylactic measures in diabetic patients may be questioned, because the inhibition of the glycation reaction between MG and proteins by high-dose L-arginine unexpectedly produces plethoric O(-)(2) as a by-product, which may subsequently aggravate the preexisting oxidative stress status of diabetic patients.

Arginine↗
PubMed1992

Concentrations of D-lactate and its related metabolic intermediates in liver, blood, and muscle of diabetic and starved rats.

This is a report investigating the methylglyoxal (MG) bypass in animals, by which D-lactate is produced from triosephosphate via MG. Rats were made diabetic using streptozotocin or starved for 72 h. D-Lactate and various metabolites related to it, such as L-lactate, pyruvate, methylglyoxal, glucose, and inorganic phosphate, were measured in the blood plasma, liver, and skeletal muscle of the rats. Diabetic and starved rats had significantly higher levels of D-lactate in plasma, liver, and skeletal muscle compared with the control group. In contrast, pyruvate levels in plasma, liver, and skeletal muscle was markedly lower than normal in diabetic and starved rats. L-Lactate level lowered markedly in plasma, liver, and skeletal muscle of starved rats and elevated in liver of diabetic rats. Differences between plasma L-lactate level for diabetes and control were not significant. MG level was significantly elevated in plasma and depressed in livers and muscles of starved rats as well as livers of diabetic rats. Hepatic glycerol content was markedly increased in those states. Enzyme activities related to D- and L-lactate, such as pyruvate kinase, phosphofructokinase, aldolase, and glyoxalase I, were measured in the livers of these rats. Pyruvate kinase activity decreased in these states, but other enzyme activities showed no significant changes. D-Lactate was much more excreted than L-lactate in the urine of diabetic and fasted rats compared with normal rats.

Animals↗
PubMed1996

Changes in concentrations of methylglyoxal, D-lactate and glyoxalase activities in liver and plasma of rats fed a 3'-methyl-4-dimethylaminoazobenzene-rich diet.

Donryu male albino rats were fed a diet containing 0.064% 3'-methyl-4-dimethylaminoazobenzene (MDAB) for 21 weeks. During the ensuing rat liver carcinogenesis, changes in the concentrations of methylglyoxal, D-lactate and glutathione as well as activities of glyoxalase I and II in liver and plasma were examined. After the start of the diet, hepatic contents of methylglyoxal and D-lactate increased to about 7 and 3 times that of the control, respectively. However, after 21 weeks the D-lactate content decreased from the elevated level, but remained at a higher level of 1.4 times the control. The hepatic glyoxalase I activity increased 1.2 to 1.7 times over the control during carcinogenesis, while glyoxalase II activity increased 160% during the precancerous state and decreased to 55% of control at 21 weeks. the hepatic level of reduced glutathione (GSH) increased and peaked after 4 weeks of the MDAB diet and decreased thereafter to 57% of the control level after 21 weeks. Both pyruvate and L-lactate levels increased in the liver and plasma of MDAB-fed rats when rats had obvious symptoms of hepatoma.

Alanine Transaminase↗
PubMed2005

The carbonyl scavengers aminoguanidine and tenilsetam protect against the neurotoxic effects of methylglyoxal.

Advanced glycation end products (AGEs) have been identified in age-related intracellular protein deposits of Alzheimer's disease (amyloid plaques and neurofibrillary tangles) and Parkinson disease (Lewy bodies), suggesting that these protein deposits have been exposed to AGE precursors such as the reactive dicarbonyl compound methylglyoxal. In ageing tissue and under diabetic pseudohypoxia, intracellular methylglyoxal levels rise through an impairment of triosephosphate utilization. Furthermore, methylglyoxal detoxification is impaired when reduced glutathione levels are low, conditions, which have all been described in Alzheimer's disease. However, there is less known about the toxicity of methylglyoxal, particularly about therapeutic strategies to scavenge such dicarbonyl compounds and attenuate their toxicity. In our study, extracellularly applied methylglyoxal was shown to be toxic to human neuroblastoma cells in a dose-dependent manner above concentrations of 150 microM with a LD50 of approximately 1.25 mM. Pre-incubation of methylglyoxal with a variety of carbonyl scavengers such as aminoguanidine or tenilsetam and the thiol antioxidant lipoic acid significantly reduced its toxicity. In summary, carbonyl scavengers might offer a promising therapeutic strategy to reduce the neurotoxicity of reactive carbonyl compounds, providing a potential benefit for patients with age-related neurodegenerative diseases.

Cell Line, Tumor↗
PubMed2005

Renal clearance of glycolaldehyde- and methylglyoxal-modified proteins in mice is mediated by mesangial cells through a class A scavenger receptor (SR-A).

AIMS/HYPOTHESIS: Glomerular mesangial expansion is a characteristic feature of diabetic nephropathy, and the accumulation of AGE in the mesangial lesion has been implicated as one of its potential causes. However, the route for the AGE accumulation in mesangial lesions in diabetic patients is poorly established. METHODS: Glycolaldehyde-modified BSA (GA-BSA) and methylglyoxal-modified BSA (MG-BSA) were prepared as model AGE proteins, and their in vivo plasma clearance was examined in mice, and renal uptake by in vitro studies with isolated renal mesangial cells. RESULTS: Both (111)In-GA-BSA and (111)In-MG-BSA were rapidly cleared from the circulation mainly by both the liver and kidney. Immunohistochemical studies with an anti-GA-BSA antibody demonstrated that intravenously injected GA-BSA accumulated in mesangial cells, suggesting that such cells play an important role in the renal clearance of circulating AGE proteins. Binding experiments at 4 degrees C using mesangial cells isolated from mice showed that (125)I-GA-BSA and (125)I-MG-BSA exhibited specific and saturable binding. Upon incubation at 37 degrees C, (125)I-GA-BSA and (125)I-MG-BSA underwent endocytic degradation by these cells. The binding of the ligands to these cells was inhibited by several ligands for scavenger receptors. The endocytic degradation of GA-BSA by mesangial cells from class A scavenger receptor (SR-A) knock-out mice was reduced by 80% when compared with that of wild-type cells. The glomerular accumulation of GA-BSA after its intravenous administration was attenuated in SR-A knock-out mice, as evidenced by immunohistochemical observations. CONCLUSIONS/INTERPRETATION: These results raise the possibility that circulating AGE-modified proteins are subjected to renal clearance by mesangial cells, mainly via SR-A. This pathway may contribute to the pathogenesis of AGE-induced diabetic nephropathy.

Acetaldehyde↗
PubMed2005

Glycation of low-density lipoproteins by methylglyoxal and glycolaldehyde gives rise to the in vitro formation of lipid-laden cells.

AIMS/HYPOTHESIS: Previous studies have implicated the glycoxidative modification of low-density lipoprotein (LDL) by glucose and aldehydes (apparently comprising both glycation and oxidation), as a causative factor in the elevated levels of atherosclerosis observed in diabetic patients. Such LDL modification can result in unregulated cellular accumulation of lipids. In previous studies we have characterized the formation of glycated, but nonoxidized, LDL by glucose and aldehydes; in this study we examine whether glycation of LDL, in the absence of oxidation, gives rise to lipid accumulation in arterial wall cell types. METHODS: Glycated LDLs were incubated with macrophage, smooth muscle, or endothelial cells. Lipid loading was assessed by HPLC analysis of cholesterol and individual esters. Oxidation was assessed by cholesterol ester loss and 7-ketocholesterol formation. Cell viability was assessed by lactate dehydrogenase release and cell protein levels. RESULTS: Glycation of LDL by glycolaldehyde and methylglyoxal, but not glucose (in either the presence or absence of copper ions), resulted in cholesterol and cholesterol ester accumulation in macrophage cells, but not smooth muscle or endothelial cells. The extent of lipid accumulation depends on the degree of glycation, with increasing aldehyde concentration or incubation time, giving rise to greater extents of particle modification and lipid accumulation. Modification of lysine residues appears to be a key determinant of cellular uptake. CONCLUSIONS/INTERPRETATION: These results are consistent with LDL glycation, in the absence of oxidation, being sufficient for rapid lipid accumulation by macrophage cells. Aldehyde-mediated "carbonyl-stress" may therefore facilitate the formation of lipid-laden (foam) cells in the artery wall.

Acetaldehyde↗
PubMed2007

The impact of glycation on apolipoprotein A-I structure and its ability to activate lecithin:cholesterol acyltransferase.

AIMS/HYPOTHESIS: Hyperglycaemia, one of the main features of diabetes, results in non-enzymatic glycation of plasma proteins, including apolipoprotein A-I (apoA-I), the most abundant apolipoprotein in HDL. The aim of this study was to determine how glycation affects the structure of apoA-I and its ability to activate lecithin:cholesterol acyltransferase (LCAT), a key enzyme in reverse cholesterol transport. MATERIALS AND METHODS: Discoidal reconstituted HDL (rHDL) containing phosphatidylcholine and apoA-I ([A-I]rHDL) were prepared by the cholate dialysis method and glycated by incubation with methylglyoxal. Glycation of apoA-I was quantified as the reduction in detectable arginine, lysine and tryptophan residues. Methylglyoxal-AGE adduct formation in apoA-I was assessed by immunoblotting. (A-I)rHDL size and surface charge were determined by non-denaturing gradient gel electrophoresis and agarose gel electrophoresis, respectively. The kinetics of the LCAT reaction was investigated by incubating varying concentrations of discoidal (A-I)rHDL with a constant amount of purified enzyme. The conformation of apoA-I was assessed by surface plasmon resonance. RESULTS: Methylglyoxal-mediated modifications of the arginine, lysine and tryptophan residues in lipid-free and lipid-associated apoA-I were time- and concentration-dependent. These modifications altered the conformation of apoA-I in regions critical for LCAT activation and lipid binding. They also decreased (A-I)rHDL size and surface charge. The rate of LCAT-mediated cholesterol esterification in (A-I)rHDL varied according to the level of apoA-I glycation and progressively decreased as the extent of apoA-I glycation increased. CONCLUSIONS/INTERPRETATION: It is concluded that glycation of apoA-I may adversely affect reverse cholesterol transport in subjects with diabetes.

Apolipoprotein A-I↗
PubMed1999

Diabetic retinopathy risk correlates with intracellular concentrations of the glycoxidation product Nepsilon-(carboxymethyl) lysine independently of glycohaemoglobin concentrations.

AIMS/HYPOTHESIS: We investigated whether either the amount of diabetes-induced intracellular oxidative stress or the concentration of hyperglycaemia-induced advanced glycation endproducts is associated with the risk of diabetic retinopathy. METHODS: We measured concentrations of the glycoxidation product Nepsilon-(carboxymethyl)lysine and two non-oxidation-dependent advanced glycation end-products (methylglyoxal-derived and 3-deoxyglucosone-derived) in CD45RA+ T-cells from 21 Type I (insulin-dependent) diabetic patients with and without diabetic retinopathy and from age-matched nondiabetic control subjects. RESULTS: Intracellular concentrations of both oxidation-dependent Nepsilon-(carboxymethyl)lysine and oxidation-independent advanced glycation endproducts were increased in memory T-cells from diabetic patients. Nepsilon-(carboxymethyl)lysine: diabetic median-24176 arbitrary units/mg protein (95% confidence interval 18690-34099 arbitrary units/mg protein); nondiabetic-9088 arbitrary units/mg protein (confidence interval 6994-10696 arbitrary units/mg protein; p < 0.0001). Methylglyoxal-derived advanced glycation end products: diabetic-5430 arbitrary units/ mg protein (confidence interval 3458-13610); nondiabetic-271 arbitrary units/mg protein (confidence interval 61-760 arbitrary units/mg protein; p< 0.0001). 3-Deoxyglucosone-derived advanced glycation end products: diabetic-8070 arbitrary units/mg protein (confidence interval 7049-16551 arbitrary units/mg protein); nondiabetic-1479 arbitrary units/ mg protein (confidence interval 1169-3170; p< 0.0001). Only Nepsilon-(carboxymethyl)lysine concentrations, however, inversely correlated with the duration of retinopathy-free diabetes (r = -0.51; p < 0.02). Diabetes-dependent Nepsilon-(carboxymethyl)lysine accumulation did not correlate with age, diabetes duration, or averaged glycohaemoglobin concentrations. In vitro experiments wih menadione and lymphocytes confirmed that Nepsilon-(carboxymethyl)lysine concentrations reflect intracellular oxidative stress. CONCLUSION/INTERPRETATION: Monitoring intracellular concentrations of increased oxidative stress in long-lived CD45RA+ lymphocytes by markers such as Nepsilon-(carboxymethyl)lysine possibly identifies a subgroup of patients at high risk for microvascular complications.

Adult↗
PubMed1998

Methylglyoxal production in bacteria: suicide or survival?

Methylglyoxal is a toxic electrophile. In Escherichia coli cells, the principal route of methylglyoxal production is from dihydroxyacetone phosphate by the action of methylglyoxal synthase. The toxicity of methylglyoxal is believed to be due to its ability to interact with the nucleophilic centres of macromolecules such as DNA. Bacteria possess an array of detoxification pathways for methylglyoxal. In E. coli, glutathione-based detoxification is central to survival of exposure to methylglyoxal. The glutathione-dependent glyoxalase I-II pathway is the primary route of methylglyoxal detoxification, and the glutathione conjugates formed can activate the KefB and KefC potassium channels. The activation of these channels leads to a lowering of the intracellular pH of the bacterial cell, which protects against the toxic effects of electrophiles. In addition to the KefB and KefC systems, E. coli cells are equipped with a number of independent protective mechanisms whose purpose appears to be directed at ensuring the integrity of the DNA. A model of how these protective mechanisms function will be presented. The production of methylglyoxal by cells is a paradox that can be resolved by assigning an important role in adaptation to conditions of nutrient imbalance. Analysis of a methylglyoxal synthase-deficient mutant provides evidence that methylglyoxal production is required to allow growth under certain environmental conditions. The production of methylglyoxal may represent a high-risk strategy that facilitates adaptation, but which on failure leads to cell death. New strategies for antibacterial therapy may be based on undermining the detoxification and defence mechanisms coupled with deregulation of methylglyoxal synthesis.

Antiporters↗
PubMed1999

Methylglyoxal causes swelling and activation of a volume-sensitive anion conductance in rat pancreatic beta-cells.

Membrane potential and whole-cell current were studied in rat pancreatic beta-cells using the 'perforated patch' technique and cell volume measured by a video-imaging method. Exposure of beta-cells to the alpha-ketoaldehyde methylglyoxal (1 mM) resulted in depolarization and electrical activity. In cells voltage-clamped at -70 mV, this effect was accompanied by the development of inward current noise. In voltage-pulse experiments, methylglyoxal activated an outwardly rectifying conductance which was virtually identical to the volume-sensitive anion conductance previously described in these cells. Two inhibitors of this conductance, 4,4'-dithiocyanatostilbene-2,2'-disulfonic acid (DIDS) and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), also inhibited the depolarization and inward current evoked by methylglyoxal. Methylglyoxal increased beta-cell volume to a relative value of 1.33 after 10 min with a gradual return towards basal levels following withdrawal of the alpha-ketoaldehyde. None of the effects of methylglyoxal was observed in response to t-butylglyoxal which, unlike methylglyoxal, is a poor substrate for the glyoxalase pathway. Methylglyoxal had no apparent effect on beta-cell K+ channel activity. It is suggested that the metabolism of methylglyoxal to D-lactate causes beta-cell swelling and activation of the volume-sensitive anion channel, leading to depolarization. These findings could be relevant to the stimulatory action of D-glucose, the metabolism of which generates significant quantities of L-lactate.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2002

A possible regulatory role of glyoxalase I in cell viability of human prostate cancer.

A role of glyoxalase I (Gly-I), a detoxifying enzyme, in cell viability of prostate cancer was investigated. Cell extracts obtained from 66 prostate tissue specimens and prostatic cancer PC-3 cells were assayed for Gly-I activity using the spectrophotometric method. Gly-I activity was consistently more than eightfold higher in prostate cancer (CAP) specimens (n = 37) than in non-cancerous (NCP) specimens (n = 29). To understand the importance of such a high Gly-I activity in CAP specimens, the effects of methylglyoxal (MG) on PC-3 cells were examined in vitro. MG, a putative toxic glycolytic metabolite, was capable of inducing severe (> 99%) cell death in 24 h, along with a significant reduction in activities of Gly-I as well as glyceraldehyde 3-phosphate dehydrogenase (G3PDH), a key glycolytic enzyme. However, such severe cell death was effectively (approximately 85%) prevented with N-acetylcysteine (NAC), a precursor of reduced glutathione (GSH) that is an essential cofactor for Gly-I, accompanied by the intact Gly-I and G3PDH activities. Therefore, Gly-I may play a critical detoxifying role in glycolysis to maintain cellular activity and viability of prostatic cancer cells.

Acetylcysteine↗
PubMed2001

Highly efficient Aerococcus viridans L-alpha-glycerophosphate oxidase production in the presence of H2O2-decomposing agent: purification and kinetic characterization.

Glycerophosphate oxidase was purified from Aerococcus viridans cells by phase partitioning in Triton X-114, ammonium sulfate fractionation, FPLC ion-exchange chromatography and FPLC hydrophobic-interaction chromatography. The purification achieved from a crude extract of A. viridans was 38-fold with a 32% recovery of activity. Under the growth conditions used, A. viridans strain CECT 978 proved to be an excellent glycerophosphate-oxidase producer, with enzyme production 2,800-fold greater than that described in the literature for the same microorganism. The culture medium used in the present work is that commonly used for cultivation of this microorganism, except that an H2O2-decomposing enzyme was added. The addition of catalase to the growth medium had a clear effect on the growth rate. Furthermore, methylglyoxal, a metabolite that is formed enzymatically from triose phosphates, was found to be an inactivator of glycerophosphate oxidase activity.

Catalase↗
PubMed2004

Functional characterisation of glyoxalase I from the fungal wheat pathogen Stagonospora nodorum.

During an expressed sequence tag sequencing project, a gene encoding a methylglyoxal lyase (glyoxalase I) was identified, cloned and characterised from the necrotrophic wheat pathogen Stagonospora nodorum. Sequence analysis identified the gene, named Gox1, as having reasonable identity to GLO1 from yeast and hypothetical proteins identified in fungal genome sequencing projects. Expression analysis in vitro revealed Gox1 to be up-regulated in the presence of methylglyoxal and salt but not affected by starvation conditions. Analysis of Gox1 transcription in planta showed its highest expression was in ungerminated spores and during sporulation, suggesting a role for the glycolytic bypass pathway in sporulation. The gene was inactivated by homologous recombination, resulting in a S. nodorum strain with no detectable glyoxalase I activity. The gox1 mutants exhibited no discernable phenotype, with the exception of being more sensitive to the presence of methylglyoxal. Infection assays demonstrated the mutants retained full pathogenicity and sporulation was unaffected. This is the first report describing the characterisation of a glyoxalase I from a pathogen of any description. The gene has been sequenced, functionally characterised and shown not to be required for the infection of wheat by S. nodorum.

Ascomycota↗
PubMed2001

The Saccharomyces cerevisiae aldose reductase is implied in the metabolism of methylglyoxal in response to stress conditions.

The enzyme aldose reductase plays an important role in the osmo-protection mechanism of diverse organisms. Here, we show that yeast aldose reductase is encoded by the GRE3 gene. Expression of GRE3 is carbon-source independent and up-regulated by different stress conditions, such as NaCl, H2O2, 39 degrees C and carbon starvation. Measurements of enzyme activity and intracellular sorbitol in wild-type cells also indicate that yeast aldose reductase is stress-regulated. Overexpression of GRE3 increases methylglyoxal tolerance in Saccharomyces cerevisiae. Furthermore, high expression of GRE3 complements the deficiency of the glyoxalase system of a glo1delta mutant strain. Consistent with this, in vitro and in vivo assays of yeast aldose reductase activity indicate that methylglyoxal is an endogenous substrate of aldose reductase. Furthermore, addition of NaCl or H2O2 to exponential-phase cells triggers an initial transient increase in the intracellular level of methylglyoxal, which is dependent on the Gre3p and Glo1p function. These observations indicate that the metabolism of methylglyoxal is stimulated under stress conditions; and they support a methylglyoxal degradative pathway, in which this compound is metabolised by the action of aldose reductase.

Aldehyde Reductase↗