Pyridoxamine, an inhibitor of advanced glycation reactions, also inhibits advanced lipoxidation reactions - Mechanism of action of pyridoxamine

Maillard or browning reactions lead to formation of advanced glycation end products (AGEs) on protein and contribute to the increase in chemical modif ication of proteins during aging and in diabetes. AGE inhibitors such as am inoguanidine and pyridoxamine (PM) have proven effective in animal model an d clinical studies as inhibitors of AGE formation and development of diabet ic complications. We report here that PM also inhibits the chemical modific ation of proteins during lipid peroxidation (lipoxidation) reactions in vit ro, and we show that it traps reactive intermediates formed during lipid pe roxidation. In reactions of arachidonate with the model protein RNase, PM p revented modification of lysine residues and formation of the advanced lipo xidation end products (ALEs) N-epsilon-(carboxymethyl)lysine, N-epsilon-(ca rboxyethyl)lysine, malondialdehyde-lysine, and 4-hydroxynonenal-lysine. PM also inhibited lysine modification and formation of ALEs during copper-cata lyzed oxidation of low density lipoprotein. Hexanoic acid amide and nonaned ioic acid monoamide derivatives of PM were identified as major products for med during oxidation of linoleic acid in the presence of PM. We propose a m echanism for formation of these products from the 9- and 13-oxo-decadienoic acid intermediates formed during peroxidation of linoleic acid. PM, as a p otent inhibitor of both AGE and ALE formation, may prove useful for limitin g the increased chemical modification of tissue proteins and associated pat hology in aging and chronic diseases, including both diabetes and atheroscl erosis.