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Home , Oxidative stress, Radical (chemistry)

part 2. mechanisms of

chapter 15. and -induced signalling John R. Bucher PART 2 CHAPTER 15

Throughout evolution, aerobic An imbalance between the normal Pierre et al., 2002). Peroxisomes are organisms have developed mul- production of radicals and a source of H2O2, through reactions tiple defence systems to protect their capture and disposal by pro- involving acyl-CoA oxidase (which themselves against oxygen radicals tective systems and antiox- is involved in oxidation of long-chain (Benzie, 2000). One-, two-, and idants results in oxidative stress, and fatty acids), d-amino acid oxidase, three-electron reductions of molecu- this condition has been proposed and other oxidases (Schrader and lar oxygen give rise to, respectively, to be the basis of many deleterious Fahimi, 2006). • − (O2 ), chronic health conditions and dis- When stimulated, inflammatory

(H2O2, a radical precursor), and the eases, including . cells such as neutrophils, eosino- highly reactive (•OH) phils, and produce ox- or equivalent –oxy- Sources of oxygen radicals ygen radicals during the associated gen complexes (Miller et al., 1990). (the rapid release of Reactions of oxygen radicals with Mitochondrial oxidative phosphor- from cells) cellular components can deplete an- ylation is a major source of oxy- that involves nicotinamide adenine tioxidants, can cause direct oxidative gen radicals of endogenous origin. dinucleotide phosphate (NADPH) damage to , , RNA, and Mitochondrial complex I (reduced oxidase (Babior, 1999). This reac- DNA, and can result in the forma- nicotinamide adenine dinucleotide tion produces superoxide, which is tion of a variety of other reactants [NADH]:ubiquinone oxidoreductase) converted by superoxide dismut- with varying oxidative potentials, in- and complex III (ubiquinol:cy- ase to the more readily diffusible cluding carbon- or -centred tochrome c oxidoreductase) are oxidant H2O2 and is involved in cell radicals (West and Marnett, 2006). sites of superoxide production, with killing functions. Inflammatory cells A growing body of literature presents as much as 1–2% of the electron such as macrophages are also ca- radicals as mediators of various cell flux shunted through one-electron pable of producing (•NO), signalling processes (Ma, 2010). reduction of molecular oxygen (St- through an inducible form of nitric

Part 2 • Chapter 15. Oxidative stress and radical-induced signalling 153 oxide synthase (Hibbs et al., 1988). product 8-oxo-2′-deoxyguanosine is Oxygen radicals in cancer •NO is also involved in cell killing but often used as a marker of oxidative Hanahan and Weinberg (2011), in can also react with superoxide at DNA damage, although other bas- their landmark review “Hallmarks diffusion-limited rates to form per- es are also susceptible to oxidation. of cancer: the next generation”, oxynitrite, a potent oxidant with a DNA bases can be modified by lip- identified sustaining proliferative longer half-life and diffusion distance id peroxidation reaction products signalling, reprogramming of en- than the hydroxyl radical (Beckman, (trans-4-hydroxy-2-nonenal, 4-hy- ergy , evading growth 1996). droperoxy-2-nonenal, and malondi- suppressors and immune destruc- Exogenous agents are also impli- ) to form various pro-mu- tion, resisting cell , enabling cated in the generation of reactive tagenic exocyclic adducts (Bartsch replicative immortality, inducing oxygen. Metals such as cadmium and Nair, 2006). angiogenesis, and activating inva- and arsenic can participate in reac- sion and as signal trans- tions that generate oxygen radicals Defence mechanisms duction pathways key to unravelling (Liu et al., 2008; Kojima et al., 2009). Cytosolic and mitochondrial forms the cancer phenotype. They also Miller et al. (1990) presented a list of of catalyse described how genomic instability endogenous and exogenous agents the reduction of superoxide to H O , and tumour-promoting inflammation that are capable of reducing oxygen 2 2 and when coupled with are principal drivers of these events. to superoxide or that “autoxidize”, within peroxisomes or with cytosolic Oxygen radicals clearly contribute to probably through reactions catalysed peroxidase, can further genomic instability, are produced by by transition metals. Metabolism of convert these reactive species to inflammation, and – along with oth- many exogenous agents through cy- water (Benzie, 2000). Sequestration er radical species – play key roles tochrome P450-mediated reactions in many of the processes identified can also result in the release of ox- of transition metals, principally above as necessary for conversion ygen radicals (Hrycay and Bandiera, and , in their oxidized forms of normal cells into cancer cells. 2015), as can exposure to ionizing through deposition in transport or Oxidative damage is considered . In addition, several life- storage proteins, or as chelates to be a major factor in the generation style factors, such as obesity, tobac- that do not support reactions, of , which are estimated to also limits radical reactions (Hatcher co smoking, and consump- occur at a frequency of 10 000 per et al., 2009). tion, as well as chronic inflammatory cell per day in (Lu et al., Dietary and endogenously pro- conditions and viral are 2001). More than 100 different oxi- duced also contribute in thought to involve radical-induced dative DNA lesions (Klaunig et al., the defence against radical damage injury (Mena et al., 2009). 2011) and at least 24 base modifica- by serving as radical scavengers. tions (Wilson et al., 2003) have been Oxidative damage Theoretically any oxidizable sub- identified, along with DNA– strate can act as a radical ; The hydroxyl radical or equivalent cross-links (Cadet et al., 1997), all ascorbic acid, , , transition metal–oxygen complexes of which potentially to genomic (Bucher et al., 1983) are highly re- and sulfhydryl-containing amino ac- instability. RNA has also been shown active entities, capable of abstract- ids provide considerable scavenging to be susceptible to radical attack (Li ing electrons from lipids, proteins, capacity (Benzie, 2000). et al., 2006) but may be less chem- or DNA (Miller et al., 1990), and the Interestingly, high concentrations ically susceptible than DNA (Thorp, resulting target radical of antioxidants in the presence of 2000). Oxidative damage to DNA can then combine with molecular transition metals can actually drive can lead to point mutations, dele- oxygen to participate in subsequent formation of oxygen radicals (Tien tions, insertions, or chromosomal radical reactions, such as propaga- et al., 1982). The importance of a translocations, which may cause tion of peroxidation. Radical balance between pro- and antioxid- activation of oncogenes and inacti- reactions with DNA result in single- ant capacities is also emphasized vation of tumour suppressor genes and double-strand breaks (Toyokuni by an emerging understanding of and may lead to initiation of carcino- and Sagripanti, 1996), cross-links, the role of radical species in cellular genesis (reviewed by Bartsch and and modified bases. The oxidation . Nair, 2006; Klaunig et al., 2011).

154 Clearly, high levels of oxygen rad- tions of glutathione peroxidases neonates of certain of these species icals can be fatal to the cell through along with thyroid peroxidase, to survive such exposures with little overt or the induction of and high levels of glutathione per- evidence of injury. The neonates of , but lower levels may also oxidases can interfere with the species resistant to pulmonary injury contribute to the process of carcino- synthesis of thyroid hormones. are capable of increasing their levels genesis through stimulation of cellu- Immunostaining for 8-oxo-2′-deoxy- of in response lar proliferation and alterations in oth- guanosine shows greater intensity in to , in contrast to the adults, er cellular functions. There appear to thyroid follicular cells near the lumen which are incapable of mounting a be a myriad of potential mechanisms where H2O2 is generated than in the similar response (Frank et al., 1978). for these effects, involving induction spleen, , or , suggesting a Several metals, metalloids, and of transcription factors for numer- high level of oxidative DNA damage fibres that contain metals or are fre- ous signalling pathways, particular- in the thyroid (Maier et al., 2006). quently contaminated with metals ly nuclear factor erythroid 2-related Environmental insults may aug- have been demonstrated to cause factor 2 (Nrf2), mitogen-activated ment oxidative DNA damage in the cancer of the lung in humans and protein kinase (MAPK)/AP1, nucle- thyroid. Thyroid uptake of iodine-131 experimental animals (IARC, 2012a). ar factor kappa-light-chain-enhanc- released during the accident with the These include certain forms of ar- er of activated B cells (NF-κB), and Chernobyl Nuclear Power Plant in senic, asbestos, beryllium, cadmi- -inducible transcription fac- Ukraine is thought to be responsible um, , and nickel. Although tor 1 alpha (HIF-1α) (reviewed by for the high rate of papillary carci- carcinogenesis induced by metals PART 2 CHAPTER 15 Klaunig et al., 2011). Protein kinase noma observed in exposed children appears to involve many mecha- C, which is also susceptible to acti- (Bennett et al., 2006). Rats and mice nisms common to the process for vation by cellular oxidants, is a fam- exposed to iodine-131 develop fol- other carcinogens, oxidative stress ily of serine/threonine kinases that licular cell tumours (IARC, 2012b). has been implicated as an important is central to the regulation of many Thiocyanate from contributing factor for several met- cellular functions, including prolifer- may, by inhibiting uptake of iodine, als (reviewed by Beyersmann and ation, cell-cycle control, differentia- cause oxidative damage through Hartwig, 2008). tion, cytoskeletal organization, cell iodine deficiency. Production of Certain metals may undergo di- migration, and apoptosis (Wu, 2006). thyroid-stimulating hormone is in- rect redox cycling, as demonstrated There is also evidence that the ac- creased during periods of iodine by the participation of nickel(II) in a tivated oncogene v-Ha-Ras may act deficiency, and this hormone stimu- Fenton-like reaction with H2O2, or in as a sustained proliferative stimulus lates H2O2 production in the thyroid. the metabolism of trivalent to pen- in transformed fibroblasts through Levels of antioxidant enzymes have tavalent arsenic. Other metals, such superoxide-mediated signalling been shown to be elevated by iodine as cadmium, may inhibit antioxidant pathways (Irani et al., 1997). deficiency (Krohn et al., 2007). enzymes or deplete antioxidants The lung is also a vulnerable tar- (cadmium and arsenic bind with Vulnerable tissue sites and selected carcinogenic get for oxidative damage, by virtue sulfhydryl groups in glutathione) or exposures of its exposure to air, which contains potentially delocalize iron or copper 21% oxygen, as opposed to the from protected storage sites (e.g. tri- The synthesis of thyroid hormones much lower oxygen concentrations valent arsenic can release iron from requires iodination of thyroglobu- in systemic tissues (Carreau et al., ), making them available for lin in a peroxidase-catalysed re- 2011). A key role of oxygen radicals participation in oxygen radical reac- action that is dependent on H2O2. in the pulmonary toxicity resulting tions. Still other metals, such as ar- Krohn et al. (2007) reviewed evi- from prolonged exposure to hyper- senic (reviewed by Shi et al., 2004), dence suggesting that the thyroid is oxia is demonstrated by the dramatic may activate signalling pathways particularly sensitive to formation of difference in the sensitivity of adult through increased production of oxy- malignant nodules induced by oxida- animals of various species, which gen radicals, and potentially promote tive stress. During active hormone succumb to after less radical reactions through a variety synthesis, H2O2 levels are held in than a week of exposure to 100% of mechanisms. Finally, many stud- check with increased concentra- oxygen, compared with the ability of ies have shown that asbestos or

Part 2 • Chapter 15. Oxidative stress and radical-induced signalling 155 asbestos-like materials (respirable Summary intimately involved in many well-rec- elongated mineral particles or fibres) ognized mechanisms of carcino- are capable of generating oxygen Many substances recognized as genesis, such as inflammation, carcinogens in both humans and radicals, primarily through reactions genomic instability, and cell prolifer- experimental animals are capable ation. Because of the fundamental catalysed by iron that is present in of influencing redox processes and involvement of the oxygen radical in coordination bonding within the min- redox balance within target cells. many of these processes, substanc- eral structure, is associated with the Oxygen radicals are capable of in- es that have been shown to promote surface, or is chelated and released teracting with and influencing many cellular injury induced by oxygen from the fibre by various intracellular cellular processes believed to be radicals should be considered as pu- organic acids, such as citrate (Aust involved in the dysregulation of nor- tative carcinogens until it has et al., 2011). mal cellular physiology, thus sending been adequately demonstrated oth- the cells down the pathway to can- erwise (Bucher and Portier, 2004). cer. Oxygen radical reactions are

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Part 2 • Chapter 15. Oxidative stress and radical-induced signalling 157