Release of Superoxide from Nucleoside Peroxyl Radicals, a Double-Edged Sword?

Abstract

5,6-Dihydrothymidin-5-yl (1) and 2‘-deoxyuridin-1‘-yl (3) were independently generated in solution under aerobic conditions. The release of superoxide (O2•-) from the respective peroxyl radicals derived from 1 and 3 was determined spectrophotometrically. Competition studies enable one to estimate that the rate constant for elimination of O2•- from the peroxyl radical (4) derived from 3 is ∼1 s-1. This process is competitive with the anticipated rate of trapping of 4 in DNA by glutathione. Relative rate studies indicate that O2•- generation resulting from the formation of 1 under aerobic conditions competes effectively with trapping of the peroxyl radical by Bu3SnH. Superoxide elimination from the peroxyl radical of 1 (2) restores the damaged nucleoside to its unaltered form, implying that this reactive intermediate has a naturally occurring detoxification pathway available to it. However, the freely diffusible superoxide can react further to generate other reactive species capable of damaging nucleic acid...