Protective Effects of Carnosine and Relative Compounds on DNA Cleavage by Advanced Glycation End Products

Abstract

Three-carbon α-dicarbonyl compound, methylglyoxal (MG), is endogenous metabolite and product of triose spontaneous oxidation and acetone and aminoacetone metabolism. MG has been implicated in secondary diabetic complications promoting formation of advanced glycation end products (AGEs). MG readily reacts with protein lysine and arginine residues to produce cross-linked products. It was reported that the glycation reaction of amino acids by MG generated reactive oxygen species (ROS). The significance of ROS in damage to many biological molecules including DNA has drawn much attention. Cleavage of plasmid DNA has been efficiently induced by direct treatment with several kinds of metals plus H2O2. DNA strand breaks and DNA fragmentation induced by alloxan in pancreatic islet cells seem to play an important role in the development of diabetes. This fragmentation is also thought to result from the accumulation of ROS produced directly from alloxan. Carnosine (β-alanyl-L-histidine) and related compounds such as anserine (β-alanyl-1-methyl-L-histidine) and homocarnosine (γ-amino-butyryl-L-histidine) are present in several mammalian tissues, including skeletal muscle and brain at high concentrations (up to 20 mM in humans). Carnosine and anserine have been shown to be efficient copperchelating agents, and it has been suggested that they may play a role in copper metabolism in vivo. Carnosine also protects rabbit heart from reperfusion injury after ischemia. Many biochemical studies have suggested that carnosine possesses antioxidant and free radical-scavenging function which may partly explain it apparent homeostatic function. Recently, it has been reported that carnosine could act as an antiglycation agent. However, the inhibitory action of carnosine and related compounds against oxidative DNA cleavage by glycation reaction has not been studied. In the present study, the protective effects of carnosine and homocarnosine on DNA cleavage induced by the glycation reaction of lysine with MG in the presence of Fe was investigated.