Bilirubin/biliverdin-Cu(II) induced DNA breakage; reaction mechanism and biological significance

Abstract

Bilirubin and its metabolic precursor biliverdin are heme degradation products but have been proposed as physiological antioxidants. Reports from another laboratory as well as from ours have shown bilirubin to form a complex with the transition metal ion-Cu(II). Such a complex was shown by us to cause oxidative DNA damage. Further, biliverdin was also shown to be capable of causing similar DNA damage. In the present studies we have aimed to elucidate the mechanism of DNA breakage reaction by these bile pigments. Absorption and fluorescence studies indicate binding of bile pigments to DNA and copper ions. Cu(II) is reduced by these compounds to Cu(I) which is an essential intermediate in the DNA breakage reaction. Redox recycling of Cu(II) leads to generation of reactive oxygen species. Strand scission by the bile pigments-Cu(II) system is found to be biologically significant as assayed by bacteriophage inactivation. Our results, therefore are suggestive of one of the mechanisms through which endogenous DNA damage may occur.