Carnosine and Homocarnosine Inhibit Cytochrome c-Mediated DNA Strand Breakage

Abstract

Peroxidases are ferric haem enzymes, which catalyses the oxidation of various organic and inorganic substrates by hydrogen peroxide or related compounds. The oxidation of substrates by classical peroxidases generally proceeds through two oxoferryl intermediates, which are two and one oxidizing equivalents, respectively, above the Fe(III) state. It has been reported that the reaction between ferricytochrome c and hydrogen peroxide would initially form an oxoferryl derivative of hemeprotein. Oxoferryl cytochrome c, similar to compound I of peroxidases, is assumed to contain two oxidizing equivalents, one in the form of oxoferryl heme (Fe=O), and another as the porphyrin π radical. Highly reactive ferryl-heme species are capable of oxidizing biomolecules including DNA, protein and lipid. Oxidative damage of DNA has been hypothesized to play a critical role in several diverse biological processes including mutagenesis, aging, carcinogenesis, radiation effects and cancer chemotherapy. Carnosine, a naturally occurring dipeptide (β-alanyl-Lhistidine), is found predominantly in long-lived tissues including the brain, innervated muscle, and the lens in high amounts (up to 20 mM in human muscle). Carnosine can delay senescence and extend the life-span of cultured human fibroblasts, kill transformed cells, and protect cells against aldehydes and an amyloid peptide fragment. The imidazolium group of histidine or carnosine stabilizes adducts formed at the primary amino group and may play an important role for an anticrosslinking agent. Many biochemical studies have suggested that carnosine possesses antioxidant and free radical-scavenging function which may partly explain it apparent homeostatic function. However, the inhibitory action of carnosine and related compounds against cytochrome c-mediated DNA damage has not been reported. In the current study, we examined the protective effect of carnosine and homocarnosine on the cytochrome c/ H2O2 system-mediated DNA strand breakage.