Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer.

It is increasingly proposed that reactive oxygen species (ROS) and reactive nitrogen species (RNS) play a key role in human cancer development [1–6], especially as evidence is growing that antioxidants may prevent or delay the onset of some types of cancer (reviewed in [7,8]). ROS is a collective term often used by biologists to include oxygen radicals [superoxide (O # J−), hydroxyl (OHJ), peroxyl (RO # J) and alkoxyl (ROJ)] and certain nonradicals that are either oxidizing agents and}or are easily converted into radicals, such as HOCl, ozone (O $ ), peroxynitrite (ONOO−), singlet oxygen ("O # ) and H # O # . RNS is a similar collective term that includes nitric oxide radical (NOJ), ONOO−, nitrogen dioxide radical (NO # J), other oxides of nitrogen and products arising when NOJ reacts with O # J−, ROJ and RO # J. ‘Reactive ’ is not always an appropriate term; H # O # , NOJ and O # J− react quickly with very few molecules, whereas OHJ reacts quickly with almost anything. RO # J, ROJ, HOCl, NO # J, ONOO− and O $ have intermediate reactivities. ROS and RNS have been shown to possess many characteristics of carcinogens [4] (Figure 1). Mutagenesis by ROS}RNS could contribute to the initiation of cancer, in addition to being important in the promotion and progression phases. For example, ROS}RNS can have the following effects. (1) Cause structural alterations in DNA, e.g. base pair mutations, rearrangements, deletions, insertions and sequence amplification. OHJ is especially damaging, but "O # , RO # J, ROJ, HNO # , O $ , ONOO− and the decomposition products of ONOO− are also effective [9–13]. ROS can produce gross chromosomal alterations in addition to point mutations and thus could be involved in the inactivation or loss of the second wild-type allele of a mutated proto-oncogene or tumour-suppressor gene that can occur during tumour promotion and progression, allowing expression of the mutated phenotype [4]. (2) Affect cytoplasmic and nuclear signal transduction pathways [14,15]. For example, H # O # (which crosses cell and organelle membranes easily) can lead to displacement of the inhibitory subunit from the cytoplasmic transcription factor nuclear factor κB, allowing the activated factor to migrate to the nucleus [14]. Nitration of tyrosine residues by ONOO− may block phosphorylation. (3) Modulate the activity of the proteins and genes that respond to stress and which act to regulate the genes that are related to cell proliferation, differentiation and apoptosis [4,14–17]. For example, H # O # can stimulate transcription of c-jun