title: Effect of pyridoxamine on chemical modification of proteins by carbonyls in diabetic rats: characterization of a major product from the reaction of pyridoxamine and methylglyoxal.
abstract: Advanced glycation end products (AGEs) from the Maillard reaction contribute to protein aging and the pathogenesis of age- and diabetes-associated complications. The alpha-dicarbonyl compound methylglyoxal (MG) is an important intermediate in AGE synthesis. Recent studies suggest that pyridoxamine inhibits formation of advanced glycation and lipoxidation products. We wanted to determine if pyridoxamine could inhibit MG-mediated Maillard reactions and thereby prevent AGE formation. When lens proteins were incubated with MG at 37 degrees C, pH 7.4, we found that pyridoxamine inhibits formation of methylglyoxal-derived AGEs concentration dependently. Pyridoxamine reduces MG levels in red blood cells and plasma and blocks formation of methylglyoxal-lysine dimer in plasma proteins from diabetic rats and it prevents pentosidine (an AGE derived from sugars) from forming in plasma proteins. Pyridoxamine also decreases formation of protein carbonyls and thiobarbituric-acid-reactive substances in plasma proteins from diabetic rats. Pyridoxamine treatment did not restore erythrocyte glutathione (which was reduced by almost half) in diabetic animals, but it enhanced erythrocyte glyoxalase I activity. We isolated a major product of the reaction between MG and pyridoxamine and identified it as methylglyoxal-pyridoxamine dimer. Our studies show that pyridoxamine reduces oxidative stress and AGE formation. We suspect that a direct interaction of pyridoxamine with MG partly accounts for AGE inhibition.
authors.affiliation: Center for Vision Research, Department of Ophthalmology, Case Western Reserve University and University Hospitals of Cleveland, Wearn Building, Room 643, Cleveland, OH 44106, USA. nhr@po.cwru.edu
authors.forename: Ram H
authors.initials: RH
authors.lastname: Nagaraj
authors.forename: Pratishruti
authors.initials: P
authors.lastname: Sarkar
authors.forename: Anirudh
authors.initials: A
authors.lastname: Mally
authors.forename: Klaus M
authors.initials: KM
authors.lastname: Biemel
authors.forename: Markus O
authors.initials: MO
authors.lastname: Lederer
authors.forename: Pius S
authors.initials: PS
authors.lastname: Padayatti
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D003459:Crystallins / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D019281:Dimerization; D004912:Erythrocytes / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007791:Lactoylglutathione Lyase / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D015416:Maillard Reaction; D008956:Models, Chemical; D018384:Oxidative Stress; D011733:Pyridoxamine / Q000494:pharmacology*; D011765:Pyruvaldehyde / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances
chemical_list: D003459:Crystallins; D017127:Glycation End Products, Advanced; D017392:Thiobarbituric Acid Reactive Substances; D011733:Pyridoxamine; D011765:Pyruvaldehyde; D001120:Arginine; C062187:pentosidine; D007791:Lactoylglutathione Lyase; D005978:Glutathione; D008239:Lysine