Mechanism of protection by natural antioxidant ergothioneine against copper-induced oxidative damage to DNA and protein

Ergothioneine is a naturally occurring amino acid found in up to millimolar concentrations in several biological tissues and fluids. The biological functions of ergothioneine are not completely understood. In this study, the role of ergothioneine in copper-induced oxidative damage to DNA and proteins was investigated using the following two copper-containing systems: Cu(II) with ascorbate and Cu(II) with H 2 O 2 . Strand breakage and protein carbonyl formation were used as indicators of oxidative damage to DNA and bovine serum albumin, respectively. Ergothioneine provided strong, dose-dependent protection against oxidation of DNA and proteins in both copper-containing systems. By contrast, only limited protection was observed with the hydroxyl radical scavengers dimethyl sulfoxide and mannitol, even with the scavengers at concentrations as high as 100 mmol/L. UV-visible spectroscopy and low-temperature electron spin resonance spectroscopy showed ergothioneine significantly inhibited copper-catalyzed oxidation of ascorbate and competed effectively with histidine and 1,10-phenanthroline for binding of Cu(I) but not Cu(II). In conclusion, ergothioneine is a potent, natural, sulfur-containing antioxidant that prevents copper-dependent oxidative damage to biological macromolecules by forming a redox-inactive ergothioneine-copper complex.