Chelating Activity of Advanced Glycation End-product
Inhibitors*
David L.
Price,
Patricia M.
Rhett,
Suzanne R.
Thorpe, and
John W.
Baynes
From the Department of Chemistry and Biochemistry, University of
South Carolina, Columbia, South Carolina 29208
The advanced glycation end-product (AGE)
hypothesis proposes that accelerated chemical modification of proteins
by glucose during hyperglycemia contributes to the pathogenesis of
diabetic complications. The two most commonly measured AGEs,
N
-(carboxymethyl)lysine and pentosidine, are
glycoxidation products, formed from glucose by sequential glycation and
autoxidation reactions. Although several compounds have been developed
as AGE inhibitors and are being tested in animal models of diabetes and
in clinical trials, the mechanism of action of these inhibitors is
poorly understood. In general, they are thought to function as
nucleophilic traps for reactive carbonyl intermediates in the formation
of AGEs; however alternative mechanisms of actions, such as chelation, have not been rigorously examined. To distinguish between the carbonyl
trapping and antioxidant activity of AGE inhibitors, we have measured
the chelating activity of the inhibitors by determining the
concentration required for 50% inhibition of the rate of
copper-catalyzed autoxidation of ascorbic acid in phosphate buffer. All
AGE inhibitors studied were chelators of copper, as measured by
inhibition of metal-catalyzed autoxidation of ascorbate. Apparent
binding constants for copper ranged from ~2 mM for
aminoguanidine and pyridoxamine, to 10-100 µM for
carnosine, phenazinediamine, OPB-9195 and tenilsetam. The AGE-breakers,
phenacylthiazolium and phenacyldimethylthiazolium bromide, and their
hydrolysis products, were among the most potent inhibitors of ascorbate
oxidation. We conclude that, at millimolar concentrations of AGE
inhibitors used in many in vitro studies, inhibition of AGE
formation results primarily from the chelating or antioxidant activity
of the AGE inhibitors, rather than their carbonyl trapping activity.
Further, at therapeutic concentrations, the chelating activity of
AGE inhibitors and AGE-breakers may contribute to their inhibition of
AGE formation and protection against development of diabetic complications.
*
This work was supported by Research Grant DK-19971 from the
NIDDKD, National Institutes of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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