Effects of metals on nucleoside hydroperoxide, a product of ionizing radiation in DNA

Abstract

Ionizing radiation causes formation of thymine hydroperoxides in DNA. Their decomposition generates more stable products and active oxygen species which may oxidize other DNA bases. We have determined the effects of free and chelated metal ions on the degradation of 5-hydroperoxymethyl-2-′-deoxyuridine (HPMdU). Two products were formed as analyzed by HPLC: 5-hydroperoxymethyl-2′-deoxyuridine (HMdU) and 5-formyl-2-t'-deoxyuridine (FdU). Sn (II) and Fe(II) caused instantenous HPMdU degradation; Sn(II) generated only HMdU, whereas Fe(II) formed about equal amounts of both. Sn(IV) and Fe(II) were inactive. Cu(I), Cu(II), and Co(II) caused a time-dependent formation of both products, with FdU predominating. In the presence of Cu(I), Cu(II), and Fe(II), formate inhibited formation of HMdU but enhanced that of FdU. EDTA abolished Cu(I)-induced decomposition of HPMdU but only decreased that which was mediated by Cu(II). In contrast, EDTA enhanced the activity of Fe(II) with a time-dependent formation of FdU. EDTA an diethylenetriaminepentaacetic acid (DTPA) caused an instantenous Fe(II)-mediated decomposition of HPMdU to FdU. Only desferal partially inhibited the activity of Fe(II), whereas the activities of Cu(I), Cu(II), and Fe(III) were blocked by desferal and DTPA. Possible mechanisms of HPMdI degradation by metal ions in the absence or presence of formate or chelators as well as formation of the ·OH are discussed. © 1989.