Free radical generation in chronic infection and its implication in carcinogenesis

点击翻译按钮获取中文摘要

Excessive production of free radicals such as superoxide (O_2^<・->) and nitric oxide (NO) as well as their reaction product, peroxynitrite (ONOO^-) are known to occur during infection and inflammation. These reactive species cause oxidation and nitration of vital molecules including DNA, and hence may involve in mutagenesis and carcinogenesis. In the present study, we investigated the reaction between ONOO- and nucleic acid, particularly the products of damaged nucleic acids. We further studied the impact of ONOO^- on genomic mutation by using Sendai virus (SeV) constracted green fluorescent protein (GFP) as a marker of mutation. High performance liquid chromatography analysis showed that ONOO^- clearly nitrates guanine residues in nucleoside, RNA and DNA.Efficacy of guanine nitration in RNA was as high as that in nucleoside, and 10 times higher than that in DNA.Interestingly, nitroguanosine thus formed was found to produce O_2^<・-> to a significant extent, comparably higher than that by mitomycin C, catalyzed by cytochrome reductase system. These findings suggest that nitration of guanosine by ONOO^- further enhance cellular oxidative stress due to its potential to produce O_2^<・->. Exposure of GFP/SeV to physiologically releavant concentration of ONOO^- (0.8 μM) markedly facilitated the mutation rate of GFP/SeV compared to control GFP/SeV without ONOO^- exposure. Furthermore, in vivo mutation rate of GFP/SeV was also found to depend on NO production during infection as revealed by using NO synthase knock-out mice model. All these findings suggest that reactive nitrogen species may play an important role in infection-associated carcinogensis due to, at least in part, its genotoxic potentials.