Oxidants are major contributors to cancer and aging. Part 1 Chemistry and measurement of damage to DNA by reactive oxygen species: chemistry of free radical damage to DNA and nucleoproteins DNA damage induced by photosensitization oxidative damage - meaning and measurement. Part 2 Mechanism of DNA damage by oxidative stress: hydrogen peroxide and DNA damage oxidative stress and calcium homeostasis lipid peroxidation and cancer the role of organic peroxyl radicals carcinogenesis. Part 3 Consequences of oxidative DNA damage: enzymes that repair oxidative damage to DNA sex as a response to oxidative DNA damage oxidative stress and cell proliferation in vitro ornithine decarboxylase and tumour promotion - a role for oxidants. Part 4 Pro-oxidants and DNA damage: redox cycling drugs and DNA damage role of reactive oxygen species the mutagenicity of complex mixtures of plant origin mineral fibres, cigarette smoke and oxidative DNA damage use of DNA damage as a measure of pro-oxidant actions of antioxidant food additives and nutrient components.
The discovery of the enzymatic production of the superoxide (O2·-) radical and of the presence of superoxide dismutase (SOD) enzymes in aerobic cells led directly to the proposal that O2·- is a major factor in oxygen toxicity and that SOD constitutes an important defense against it. Systems generating the O2·- radical have been shown to have a number of damaging effects, some of which are summarized. The superoxide radical itself in organic solvents is a powerful base and nucleophile, which may have relevance to reactions taking place within the interior of cell membranes. In many cases, damage is decreased by addition not only of SOD but also of catalase, and it was proposed that O2·- and H2O2 can combine together directly to generate the highly reactive hydroxyl radical, OH·. Indeed, damage is often decreased by the scavengers of this radical, such as mannitol, sodium formate, and thiourea. In such experiments, a range of scavengers should be used and it ought to be possible to correlate the degree of protection that they offer with the known rate constants for reaction of the scavengers with OH·. Several authors proposed that the salts of transition metals could catalyze the generation of hydroxyl radical, although most direct evidence for this has come from work with iron salts.
This chapter discusses the measurement of iron and copper in biological systems. It focuses on bleomycin and copper-phenanthroline assays. Bleomycin is an antitumor antibiotic produced by fermentation of Streptomyces verticillus. Clinical preparations of bleomycin are active against several human cancers including Hodgkin's disease and cancer of the testes. Bleomycins are a family of glycopeptide antibiotics, which are able to chelate metal ions through their secondary amide groups. The clinical effects are thought to be because of binding of bleomycin to DNA adjacent to guanosine residues, where it interferes with helix unwinding, replication, and transcription and may cause both single- and double-strand breakages. Additionally, degradation of deoxyribose occurs, forming several products among, which are base propenals that further break down to release the three-carbon aldehyde malondialdehyde. The chelating agent 1,10-phenanthroline degrades DNA in the presence of copper ions, O2, and a suitable reducing agent by a mechanism known to involve oxygen radicals, probably •OH. As in bleomycin-mediated DNA degradation, the deoxyribose moieties of the DNA are attacked, resulting in the formation of malondialdehyde that may be quantitated in the thiobarbituric acid (TBA) test.
Peroxynitrite (ONOO − ) is a ‘reactive nitrogen species’ that can be formed (among other reactions) by combination of superoxide (O 2 ·− ) and nitric oxide (NO · ) radicals. It is being increasingly proposed as a contributor to tissue injury in several human diseases. The evidence presented for peroxynitrite participation usually includes the demonstration of increased nitrotyrosine levels in the injured tissue. Indeed, this is often the only evidence presented: the assumption is that formation of nitrotyrosine is a biomarker specifically diagnostic of ONOO − production. The present article examines this assumption and concludes that nitrotyrosine is a biomarker for ‘nitrating species’ rather than being specific for ONOO − .
Infection with SARS-CoV-2 causes the coronavirus infectious disease 2019 (COVID-19), a pandemic that has, at present, infected more than 11 million people globally. Some COVID-19 patients develop a severe and critical illness, spurred on by excessive inflammation that can lead to respiratory or multiorgan failure. Numerous studies have established the unique array of cytoprotective properties of the dietary amino acid ergothioneine. Based on studies in a range of in vitro and in vivo models, ergothioneine has exhibited the ability to modulate inflammation, scavenge free radicals, protect against acute respiratory distress syndrome, prevent endothelial dysfunction, protect against ischemia and reperfusion injury, protect against neuronal damage, counteract iron dysregulation, hinder lung and liver fibrosis, and mitigate damage to the lungs, kidneys, liver, gastrointestinal tract, and testis, amongst many others. When compiled, this evidence suggests that ergothioneine has a potential application in the treatment of the underlying pathology of COVID-19. We propose that ergothioneine could be used as a therapeutic to reduce the severity and mortality of COVID-19, especially in the elderly and those with underlying health conditions. This review presents evidence to support that proposal.
Allopurinol is a scavenger of the highly reactive hydroxyl radical ( k 2 approx. 10 9 M −1 s −1 ). One product of attack of hydroxyl radical upon allopurinol is oxypurinol, which is a major metabolite of allopurinol. Oxypurinol is a better hydroxyl radical scavenger than is allopurinol ( k 2 approx. 4 × 10 9 M −1 s −1 ) and it also reacts with the myeloperoxidase‐derived oxidant hypochlorous acid. Hence the protective actions of allopurinol against reperfusion damage after hypoxia need not be entirely due to xanthine oxidase inhibition.
The measurement of F2-isoprostanes by methods utilizing mass spectrometry is widely regarded as the best currently available biomarker of lipid peroxidation. F2-isoprostanes and their metabolites can be measured accurately in plasma, urine, and other body fluids using mass spectrometric techniques, and detailed protocols have been published in several papers. However, many clinical studies and intervention studies with diets or supplements, have employed single "spot" measurements of F2-isoprostanes on either plasma/serum or urine to estimate "oxidative stress." This review examines the validity of the common assumption that plasma and urinary F2-isoprostane measurements are equivalent. It identifies scenarios where they may not be and where "spot" measurements can be misleading, with examples from the literature. We also discuss the controversial issue of whether and how F2-isoprostane levels in plasma should be standardized against lipids, and, if so, which lipids to use.
Cell culture studies have given much valuable information about mechanisms of metabolism and signal transduction and of regulation of gene expression, proliferation, senescence, and death. However, cells in culture may behave differently from cells in vivo in many ways. One of these is that cell culture imposes a state of oxidative stress on cells. I argue that cells that survive and grow in culture might use ROS‐dependent signal transduction pathways that rarely or never operate in vivo. A further problem is that cell culture media can catalyse the oxidation of compounds added to them, resulting in apparent cellular effects that are in fact due to oxidation products such as ROS. Such artefacts may have affected many studies on the effects of ascorbate, thiols, flavonoids and other polyphenolic compounds on cells in culture.
