MinireviewChemical basis of inflammation-induced carcinogenesis☆
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Production of ROS and RNS
Infection and inflammation activate a variety of inflammatory cells, which induce and activate various oxidant-generating enzymes (Fig. 2). These include NADPH oxidase and xanthine oxidase, which produce superoxide anion (O2−), inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO) from l-arginine, and myeloperoxidase (MPO), which generates hypochlorous acid (HOCl) using hydrogen peroxide (H2O2) and chloride ion (Cl−) as substrates. In the case of parasitic infections,
DNA damage by ROS and RNS
H2O2 reacts with reduced transition metals (either free or bound to macromolecules such as DNA) to generate the highly toxic hydroxyl radical (HO) or a metal–peroxide complex (Me–OOH). More than 30 different products of nucleobases and sugar moieties of DNA and RNA produced by oxidative damage have been identified [23]. The best studied include 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG), thymidine glycol, and 5-hydroxymethyl-2′-deoxyuridine. Oxidative damage can lead to single- or
Mutations caused by ROS and RNS
The most common point mutations induced by oxidative DNA damage are G:C to A:T transitions, followed by G:C to T:A [65]. The mutation spectrum is similar to that of spontaneous mutants. H2O2 plus Fe(III)–EDTA induces G:C to A:T, G:C to T:A, and G:C to C:G predominantly [66]. Fe(II)–EDTA alone causes G:C to C:G and G:C to T:A predominantly [67]. The most common G:C to A:T transition mutations may be caused by oxidative deamination of cytosine, forming 5-hydroxy-deoxycytidine,
Protein damage as an epigenetic effect of ROS and RNS on carcinogenesis
Alterations of protein structure and function induced by ROS and RNS may contribute to carcinogenesis. ROS and RNS react with proteins to modify amino acid residues by oxidation, nitrosation, nitration, and halogenation. Tyrosine residues in protein react with various RNS to form 3-nitrotyrosine (NTYR) [78], [79], [80]. MPO and EPO can also nitrate tyrosine to form NTYR using H2O2 and nitrite (NO2−) as substrates [81], [82]. Tyrosine residues in protein are also chlorinated by HOCl, human MPO,
Chemoprevention by anti-inflammatory agents and anti-oxidants
It has been reported that genetic disruption of some inflammation-associated enzymes results in inhibition of carcinogenesis. Examples include reduction of adenoma formation in the colon of COX-2-deficient APC delta716 knockout mice [111] and in iNOS-deficient APC(Min/+) mice [112], reduction of urethane-induced lung tumors in iNOS-deficient mice [113], and reduction of benign and malignant skin tumors induced by 7,12-dimethylbenz[a]anthracene plus TPA in TNF-α-deficient mice [114], [115]. In
Acknowledgements
The authors thank Dr. J. Cheney for editing the manuscript and Mrs. P. Collard for secretarial assistance.
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Related review articles are available at: 10.1016/S0003-9861(03)00372-2, 10.1016/S0003-9861(03)00284-4, and 10.1016/S0003-9861(03)00285-6.