Abstract
Maillard or browning reactions between reducing sugars and protein lead to formation of advanced glycation end products (AGEs) and are thought to contribute to the pathogenesis of diabetic complications. AGE inhibitors such as aminoguanidine and pyridoxamine (PM) inhibit both the formation of AGEs and development of complications in animal models of diabetes. PM also inhibits the chemical modification of protein by advanced lipoxidation end products (ALEs) during lipid peroxidation reactions in vitro. We show here that several PM adducts, formed in incubations of PM with linoleate and arachidonate in vitro, are also excreted in the urine of PM-treated animals. The PM adducts N-nonanedioyl-PM (derived from linoleate), N-pentanedioyl-PM, N-pyrrolo-PM, and N-(2-formyl)-pyrrolo-PM (derived from arachidonate), and N-formyl-PM and N-hexanoyl-PM (derived from both fatty acids) were quantified by liquid chromatography-mass spectrometry analysis of rat urine. Levels of these adducts were increased 5-10-fold in the urine of PM-treated diabetic and hyperlipidemic rats, compared with control animals. We conclude that the PM functions, at least in part, by trapping intermediates in AGE/ALE formation and propose a mechanism for PM inhibition of AGE/ALE formation involving cleavage of alpha-dicarbonyl intermediates in glycoxidation and lipoxidation reactions. We also conclude that ALEs derived from polyunsaturated fatty acids are increased in diabetes and hyperlipidemia and may contribute to development of long term renal and vascular pathology in these diseases.
Highlights
The mechanism by which PM causes a reduction in triglycerides in STZ-Db and fa/fa rats [11, 12] is unknown, protection against kidney disease may result from both inhibition of hyperlipidemia and trapping of intermediates in formation of AGE/ALEs
We identified 12 PM derivatives that were formed during incubation of PM with LA or AA under peroxidizing conditions in vitro
We administered PM to type 1 and type 2 diabetic rats, to obese hyperlipidemic rats, and to lean controls, and chemically characterized the six PM derivatives that were detected in the plasma and urine of animals treated with PM
Summary
The mechanism by which PM causes a reduction in triglycerides (and cholesterol) in STZ-Db and fa/fa rats [11, 12] is unknown, protection against kidney disease may result from both inhibition of hyperlipidemia and trapping of intermediates in formation of AGE/ALEs. Both mechanisms may be operative, it is clear that PM acts at least in part as a trap for intermediates in the lipoxidative modification of proteins (Figs. 4 and 5), documenting for the first time the proposed mechanism of action of an AGE or ALE inhibitor in viv
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