Pyridoxamine, an inhibitor
of advanced glycation reactions, also inhibits advanced lipoxidation
reactions. Mechanism of action of pyridoxamine.
Onorato JM, Jenkins AJ, Thorpe SR,
Baynes JW.
Department of Chemistry,
University of South Carolina,
Columbia, South Carolina 29208, USA.
J Biol Chem. 2000 Jul 14;275(28):21177-84
Abstract
Maillard or browning reactions lead
to formation of advanced glycation end products (AGEs) on protein and
contribute to the increase in chemical modification of proteins during
aging and in diabetes. AGE inhibitors such as aminoguanidine and
pyridoxamine have proven effective in animal model and clinical
studies as inhibitors of AGE formation and development of diabetic
complications. We report here that pyridoxamine also inhibits the chemical
modification of proteins during lipid peroxidation (lipoxidation)
reactions in vitro, and we show that it traps reactive intermediates
formed during lipid peroxidation. In reactions of arachidonate with the
model protein RNase, pyridoxamine prevented modification of lysine residues and
formation of the advanced lipoxidation end products (ALEs)
N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(carboxyethyl)lysine,
malondialdehyde-lysine, and 4-hydroxynonenal-lysine. Pyridoxamine also inhibited
lysine modification and formation of ALEs during copper-catalyzed
oxidation of low density lipoprotein. Hexanoic acid amide and
nonanedioic acid monoamide derivatives of pyridoxamine were identified as major
products formed during oxidation of linoleic acid in the presence of
pyridoxamine.
We propose a mechanism for formation of these products from the 9- and
13-oxo-decadienoic acid intermediates formed during peroxidation of
linoleic acid. Pyridoxamine, as a potent inhibitor of both AGE and ALE formation,
may prove useful for limiting the increased chemical modification of
tissue proteins and associated pathology in aging and chronic diseases,
including both diabetes and atherosclerosis.
