Contrasting effects of SH-compounds on oxidative DNA damage: repair and increase of damage

Abstract

The non-radical singlet oxygen (1O2) and the OH radical (.OH) are the major damaging oxidative species that can be generated inside cells during normal aerobic metabolism and by processes such as photosensitization. Both reactive oxygen species fulfill essential prerequisites to be a genotoxic agent. Due to their continuous production they represent an ever-present threat to all vital cellular molecules, especially DNA. As might be anticipated from the difference in character between these reactive species (non-radical versus radical) the pattern of DNA modifications caused by singlet oxygen is different from that produced by OH radicals. All cells possess an elaborate defense system against oxidative damage. This paper focuses mainly on the effect of thiols such as glutathione, which are thought to play a role as antioxidants. Under certain conditions thiols can repair chemically, probably by H-donation, some of the DNA damage caused by .OH; for instance breaks can be rather easily prevented in this way. This process will compete with fixation of damage by oxygen. However, there is ample evidence that H-atom donation does not always lead to 'correct' repair. Moreover under aerobic conditions thiyl peroxy radicals might increase DNA damage. Although the repair/fixation process could not be examined in the case of 1O2 yet, it could be demonstrated that reactive species can be formed out of the reaction of thiols with 1O2 capable of enhancing the number of DNA modifications such as 8-oxoguanine and single-strand breaks, probably arising from different pathways. Although it is quite clear that thiols are to some extent excellent antioxidants they possess unexpected properties which, depending on the conditions, can have genotoxic consequences.