Oxyradicals and DNA damage
TL;DR: The levels of oxidative DNA damage reported in many human tissues or in animal models of carcinogenesis exceed the levels of lesions induced by exposure to exogenous carcinogenic compounds, and it seems likely that oxidativeDNA damage is important in the etiology of many human cancers.
Abstract: A major development of carcinogenesis research in the past 20 years has been the discovery of significant levels of DNA damage arising from endogenous cellular sources. Dramatic improvements in analytical chemistry have provided sensitive and specific methodology for identification and quantitation of DNA adducts. Application of these techniques to the analysis of nuclear DNA from human tissues has debunked the notion that the human genome is pristine in the absence of exposure to environmental carcinogens. Much endogenous DNA damage arises from intermediates of oxygen reduction that either attack the bases or the deoxyribosyl backbone of DNA. Alternatively, oxygen radicals can attack other cellular components such as lipids to generate reactive intermediates that couple to DNA bases. Endogenous DNA lesions are genotoxic and induce mutations that are commonly observed in mutated oncogenes and tumor suppressor genes. Their mutagenicity is mitigated by repair via base excision and nucleotide excision pathways. The levels of oxidative DNA damage reported in many human tissues or in animal models of carcinogenesis exceed the levels of lesions induced by exposure to exogenous carcinogenic compounds. Thus, it seems likely that oxidative DNA damage is important in the etiology of many human cancers. This review highlights some of the major accomplishments in the study of oxidative DNA damage and its role in carcinogenesis. It also identifies controversies that need to be resolved. Unraveling the contributions to tumorigenesis of DNA damage from endogenous and exogenous sources represents a major challenge for the future.
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TL;DR: Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases, rheumatoid arthritis, and ageing.
12,240 citations
Cites background from "Oxyradicals and DNA damage"
...DNA damage can result in either arrest r induction of transcription, induction of signal transuction pathways, replication errors, and genomic instaility, all of which are associated with carcinogenesis Marnett, 2000; Valko et al., 2006)....
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...In addition, it has been demonstrated that hydroxypropanodeoxyguanosines (HO-PdGs) are present in human DNA (Marnett, 2000)....
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TL;DR: This review examines the evidence for involvement of the oxidative stress in the carcinogenesis process and the role of enzymatic and non-enzymatic antioxidants in the process of carcinogenesis as well as the antioxidant interactions with various regulatory factors.
5,937 citations
TL;DR: This review provides an analysis of arsenic, cadmium, chromium, lead, and mercury's environmental occurrence, production and use, potential for human exposure, and molecular mechanisms of toxicity, genotoxicity, and carcinogenicity.
Abstract: Heavy metals are naturally occurring elements that have a high atomic weight and a density at least five times greater than that of water. Their multiple industrial, domestic, agricultural, medical, and technological applications have led to their wide distribution in the environment, raising concerns over their potential effects on human health and the environment. Their toxicity depends on several factors including the dose, route of exposure, and chemical species, as well as the age, gender, genetics, and nutritional status of exposed individuals. Because of their high degree of toxicity, arsenic, cadmium, chromium, lead, and mercury rank among the priority metals that are of public health significance. These metallic elements are considered systemic toxicants that are known to induce multiple organ damage, even at lower levels of exposure. They are also classified as human carcinogens (known or probable) according to the US Environmental Protection Agency and the International Agency for Research on Cancer. This review provides an analysis of their environmental occurrence, production and use, potential for human exposure, and molecular mechanisms of toxicity, genotoxicity, and carcinogenicity.
4,407 citations
Cites background from "Oxyradicals and DNA damage"
...Although mutations of DNA, which can activate oncogenesis or inhibit tumor suppression, were traditionally thought to be crucial factors for the initiation of carcinogenesis, recent studies have demonstrated that other molecular events, such as transcription activation, signal transduction, oncogene amplification, and recombination, also constitute significant contributing factors [222, 223]....
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TL;DR: Observations to date suggest that oxidative stress, chronic inflammation, and cancer are closely linked.
3,922 citations
Cites background from "Oxyradicals and DNA damage"
...OHdG is the most widely used fingerprint of radical attack on DNA [77,78]....
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...diameters before it reacts in practice with any cellular component [76,77]....
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TL;DR: The TrxR-catalyzed regeneration of several antioxidant compounds, including ascorbic acid (vitamin C), selenium-containing substances, lipoic acid, and ubiquinone are summarized.
2,632 citations
Cites background from "Oxyradicals and DNA damage"
...This mechanism may partly explain the high prevalence of cancer in individuals exposed to oxidative stress [3,37]....
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...As the term ROS implies, intracellular production of those oxygen intermediates threatens the integrity of various biomolecules including proteins [1], lipids as well as lipoproteins involved in atherosclerosis [2], and DNA [3]....
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...ROS have been shown to be mutagenic [3,37], an effect that should be derived from chemical modification of DNA....
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References
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TL;DR: It is proposed that superoxide dismutase may protect vascular tissue stimulated to produce superoxide and NO under pathological conditions by preventing the formation of peroxynitrite.
Abstract: Superoxide dismutase reduces injury in many disease processes, implicating superoxide anion radical (O2-.) as a toxic species in vivo. A critical target of superoxide may be nitric oxide (NO.) produced by endothelium, macrophages, neutrophils, and brain synaptosomes. Superoxide and NO. are known to rapidly react to form the stable peroxynitrite anion (ONOO-). We have shown that peroxynitrite has a pKa of 7.49 +/- 0.06 at 37 degrees C and rapidly decomposes once protonated with a half-life of 1.9 sec at pH 7.4. Peroxynitrite decomposition generates a strong oxidant with reactivity similar to hydroxyl radical, as assessed by the oxidation of deoxyribose or dimethyl sulfoxide. Product yields indicative of hydroxyl radical were 5.1 +/- 0.1% and 24.3 +/- 1.0%, respectively, of added peroxynitrite. Product formation was not affected by the metal chelator diethyltriaminepentaacetic acid, suggesting that iron was not required to catalyze oxidation. In contrast, desferrioxamine was a potent, competitive inhibitor of peroxynitrite-initiated oxidation because of a direct reaction between desferrioxamine and peroxynitrite rather than by iron chelation. We propose that superoxide dismutase may protect vascular tissue stimulated to produce superoxide and NO. under pathological conditions by preventing the formation of peroxynitrite.
7,027 citations
TL;DR: This review provides a comprehensive summary on the chemical properties of 4-hydroxyalkenals and malonaldehyde, the mechanisms of their formation and their occurrence in biological systems and methods for their determination, as well as the many types of biological activities described so far.
6,456 citations
TL;DR: The spontaneous decay of DNA is likely to be a major factor in mutagenesis, carcinogenesis and ageing, and also sets limits for the recovery of DNA fragments from fossils.
Abstract: Although DNA is the carrier of genetic information, it has limited chemical stability. Hydrolysis, oxidation and nonenzymatic methylation of DNA occur at significant rates in vivo, and are counteracted by specific DNA repair processes. The spontaneous decay of DNA is likely to be a major factor in mutagenesis, carcinogenesis and ageing, and also sets limits for the recovery of DNA fragments from fossils.
5,209 citations
3,257 citations
TL;DR: DCMP and dAMP are incorporated selectively opposite 8-oxodG with transient inhibition of chain extension occurring 3' to the modified base, and the potentially mutagenic insertion of dAMP is targeted exclusively to the site of the lesion.
Abstract: Oxidative damage to DNA, reflected in the formation of 8-oxo-7-hydrodeoxyguanosine (8-oxodG), may be important in mutagenesis, carcinogenesis and the ageing process. Kuchino et al. studied DNA synthesis on oligodeoxynucleotide templates containing 8-oxodG, concluding that the modified base lacked base pairing specificity and directed misreading of pyrimidine residues neighbouring the lesion. Here we report different results, using an approach in which the several products of a DNA polymerase reaction can be measured. In contrast to the earlier report, we find that dCMP and dAMP are incorporated selectively opposite 8-oxodG with transient inhibition of chain extension occurring 3' to the modified base. The potentially mutagenic insertion of dAMP is targeted exclusively to the site of the lesion. The ratio of dCMP to dAMP incorporated varies, depending on the DNA polymerase involved. Chain extension from the dA.8-oxodG pair was efficiently catalysed by all polymerases tested.
2,145 citations