The inhibition of post-Amadori advanced glycation end product (AGE) formation by three different classes of AGE inhibitors, carbonyl group traps, chelators, and radical-trapping antioxidants, challenge the current paradigms that: 1) AGE inhibitors will not increase the formation of any AGE product, 2) transition metal ions are required for oxidative formation of AGE, and 3) screening AGE inhibitors only in systems containing transition metal ions represents a valid estimate of potential in vivo mechanisms. This work also introduces a novel multifunctional AGE inhibitor, 6-dimethylaminopyridoxamine (dmaPM), designed to function as a combined carbonyl trap, metal ion chelator, and radicaltrapping antioxidant. Other AGE inhibitors including pyridoxamine, aminoguanidine, o-phenylenediamine, dipyridoxylamine, and diethylenetriaminepentaacetic acid were also examined. The results during uninterrupted and interrupted ribose glycations show: 1) an unexpected increase in the yield of pentosidine in the presence of radical-trapping phenolic antioxidants such as Trolox and dmaPM, 2) significant formation of N ⑀ -carboxymethyllysine (CML) in the presence of strong chelators and phenolic antioxidants, which implies that there must be nonradical routes to CML, 3) prevention of intermolecular cross-links with radical-trapping inhibitors, and 4) that dmaPM shows excellent inhibition of AGE. Glucose glycations reveal the expected inhibition of pentosidine and CML with all compounds tested, but in a buffer free of trace metal ions the yield of CML in the presence of radical-trapping antioxidants was between the metal ion-free and metal ion-containing controls. Protein molecular weight analyses support the conclusion that Amadori decomposition pathways are constrained in the presence of metal ion chelators and radical traps.Nonenzymatic protein glycation by reducing sugars, such as glucose or ribose, is a complicated cascade of condensations, rearrangements, fragmentations, and oxidative modifications that lead to a plethora of compounds collectively called advanced glycation end products (AGEs) 1 (1). AGE products slowly build up and contribute to the age-dependent chemical modification of long-lived tissue proteins. Once formed, AGE products may prevent normal protein function and recognition or stimulate potentially detrimental interactions in signaling pathways (2, 3). Glycation reactions are believed to have a significant role in the progression of diabetic complications largely because of elevated levels of glucose. Indeed, the formation of AGE has been increasingly implicated in pathogenesis of diabetic complications, atherosclerosis, and Alzheimer's disease (4 -6). Inhibitors that act to reduce AGE formation may prove useful for limiting nonenzymatic protein modification associated in the pathology of these and other chronic agerelated diseases. The reaction of amino compounds, such as lysine, with reducing sugars is known as the Maillard reaction (7, 8). The "classical" or Hodge pathway begins with reversible formation of...

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