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Role of Endogenous Oxidative DNA Damage in Carcinogenesis: What Can We Learn from Repair-Deficient Mice?

  • B. Epe
Published/Copyright: June 1, 2005
Biological Chemistry
From the journal Volume 383 Issue 3-4

Abstract

Basal steadystate levels of oxidative DNA base modifications such as 7,8-dihydro-8-oxo-2deoxyguanosine (8-oxoG) are observed in all types of cells, most probably due to a continuous generation of reactive oxygen species (ROS) in the cellular oxygen metabolism, and it has long been suspected that they might play an important role in the initiation of carcinogenesis. Experimental evidence for this assumption can be obtained by studying the effects of a modulation the steadystate levels, either by in or decreasing the generation of oxidative DNA damage, on spontaneous mutation rates and cancer incidence. However, clear answers have not yet been obtained by these strategies. It is still doubtful whether an efficient reduction of the in vivo steadystate levels can achieved by application of antioxidants, and effects observed under oxidative stress conditions (i.e. increased oxidative DNA damage) are inconclusive due to the pronounced epigenetic effects of ROS on signal transduction and gene expression (tumor promotion). In addition, the reliable quantification of the basal levels of oxidative DNA modifications is still major problem. Recently, the generation of mice deficient in the repair 8-oxoG (ogg1/ mice) has opened the door for an alternative approach. Results obtained so far indicate that an increase by less than five 8-oxoG residues per 106 bp in the liver of the knockout animals is associated with a two to threefold higher spontaneous mutation frequency in transgenic genes. However, the increase in the ogg1/ mice of the steadystate level of 8-oxoG and the spontaneous mutation frequency was only observed in the liver and apparently too small to enhance the spontaneous cancer incidence significantly. The limited effect seems to be due to a backup repair system for 8-oxoG in the ogg1/ mice, and it can be expected that the inactivation of this pathway doubleknockout mice will lead to higher effects and a better assessment of the risk associated with endogenous oxidative DNA damage.

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Published Online: 2005-06-01
Published in Print: 2002-04-12

Copyright © 2002 by Walter de Gruyter GmbH & Co. KG

Articles in the same Issue

  1. Highlight: Oxidative Stress
  2. Highlight: Oxidative Stress
  3. Peroxiredoxins
  4. 15-Lipoxygenase-1: A Prooxidant Enzyme
  5. Reactive Sulfur Species: An Emerging Concept in Oxidative Stress
  6. The Pathobiochemistry of Nitrogen Dioxide
  7. Nitric Oxide and Peroxynitrite Interactions with Mitochondria
  8. Nitric Oxide and Cell Signaling Pathways in Mitochondrial-Dependent Apoptosis
  9. Fatty Acid Oxidation and Signaling in Apoptosis
  10. Oxidant-Induced Signaling: Effects of Peroxynitrite and Singlet Oxygen
  11. The 80th Anniversary of Vitamin E: Beyond Its Antioxidant Properties
  12. Role of Endogenous Oxidative DNA Damage in Carcinogenesis: What Can We Learn from Repair-Deficient Mice?
  13. Mammalian Cell Injury Induced by Hypothermia the Emerging Role for Reactive Oxygen Species
  14. The Chelatable Iron Pool in Living Cells: A Methodically Defined Quantity
  15. Dietary Flavonoids as Potential Neuroprotectants
  16. Oxidative Nerve Cell Death in Alzheimers Disease and Stroke: Antioxidants as Neuroprotective Compounds
  17. A2E and Blue Light in the Retina: The Paradigm of Age-Related Macular Degeneration
  18. Interactions of Nitric Oxide and Peroxynitrite with Low-Density Lipoprotein
  19. Non-Antioxidant Properties of Carotenoids
  20. Proteolytic Response to Oxidative Stress in Mammalian Cells
  21. Neurospora crassa Catalases, Singlet Oxygen and Cell Differentiation
  22. The Cellular Hydration State: A Critical Determinant for Cell Death and Survival
  23. Redox Regulation of Stress Signals: Possible Roles of Dendritic Stellate TRX Producer Cells (DST Cell Types)
  24. Oxidative Stress, Spermatogenesis and Fertility
  25. Postprandial Oxidative Stress
  26. [18O]-Labeled Singlet Oxygen as a Tool for Mechanistic Studies of 8-Oxo-7,8-Dihydroguanine Oxidative Damage: Detection of Spiroiminodihydantoin, Imidazolone and Oxazolone Derivatives
  27. The Specificity of Lipoxygenase-Catalyzed Lipid Peroxidation and the Effects of Radical- Scavenging Antioxidants
  28. Human Neutrophils Oxidize Low-Density Lipoprotein by a Hypochlorous Acid- Dependent Mechanism: The Role of Vitamin C
  29. Perturbation of Lipid Metabolism by Linoleic Acid Hydroperoxide in CaCo-2 Cells
  30. Irreversible Thiol Oxidation in Carbonic Anhydrase III: Protection by S-Glutathiolation and Detection in Aging Rats
  31. Green Tea Extract Protects against Early Alcohol-Induced Liver Injury in Rats
  32. Comparing β-Carotene, Vitamin E and Nitric Oxide as Membrane Antioxidants
  33. Induction of Thioredoxin Reductase Gene Expression by Peroxynitrite in Human Umbilical Vein Endothelial Cells
  34. Activation of c-Jun N-Terminal Kinase and Apoptosis in Endothelial Cells Mediated by Endogenous Generation of Hydrogen Peroxide
  35. Detection of Poly(ADP-Ribose) by Immunocytochemistry: A Sensitive New Method for the Early Identification of UVB- and H2O2-Induced Apoptosis in Keratinocytes
  36. Efficacy of HOCl Scavenging by Sulfur- Containing Compounds: Antioxidant Activity of Glutathione Disulfide?
  37. Cysteine Supplementation Prevents Unweighting-Induced Ubiquitination in Association with Redox Regulation in Rat Skeletal Muscle
https://doi.org/10.1515/BC.2002.049

Articles in the same Issue

  1. Highlight: Oxidative Stress
  2. Highlight: Oxidative Stress
  3. Peroxiredoxins
  4. 15-Lipoxygenase-1: A Prooxidant Enzyme
  5. Reactive Sulfur Species: An Emerging Concept in Oxidative Stress
  6. The Pathobiochemistry of Nitrogen Dioxide
  7. Nitric Oxide and Peroxynitrite Interactions with Mitochondria
  8. Nitric Oxide and Cell Signaling Pathways in Mitochondrial-Dependent Apoptosis
  9. Fatty Acid Oxidation and Signaling in Apoptosis
  10. Oxidant-Induced Signaling: Effects of Peroxynitrite and Singlet Oxygen
  11. The 80th Anniversary of Vitamin E: Beyond Its Antioxidant Properties
  12. Role of Endogenous Oxidative DNA Damage in Carcinogenesis: What Can We Learn from Repair-Deficient Mice?
  13. Mammalian Cell Injury Induced by Hypothermia the Emerging Role for Reactive Oxygen Species
  14. The Chelatable Iron Pool in Living Cells: A Methodically Defined Quantity
  15. Dietary Flavonoids as Potential Neuroprotectants
  16. Oxidative Nerve Cell Death in Alzheimers Disease and Stroke: Antioxidants as Neuroprotective Compounds
  17. A2E and Blue Light in the Retina: The Paradigm of Age-Related Macular Degeneration
  18. Interactions of Nitric Oxide and Peroxynitrite with Low-Density Lipoprotein
  19. Non-Antioxidant Properties of Carotenoids
  20. Proteolytic Response to Oxidative Stress in Mammalian Cells
  21. Neurospora crassa Catalases, Singlet Oxygen and Cell Differentiation
  22. The Cellular Hydration State: A Critical Determinant for Cell Death and Survival
  23. Redox Regulation of Stress Signals: Possible Roles of Dendritic Stellate TRX Producer Cells (DST Cell Types)
  24. Oxidative Stress, Spermatogenesis and Fertility
  25. Postprandial Oxidative Stress
  26. [18O]-Labeled Singlet Oxygen as a Tool for Mechanistic Studies of 8-Oxo-7,8-Dihydroguanine Oxidative Damage: Detection of Spiroiminodihydantoin, Imidazolone and Oxazolone Derivatives
  27. The Specificity of Lipoxygenase-Catalyzed Lipid Peroxidation and the Effects of Radical- Scavenging Antioxidants
  28. Human Neutrophils Oxidize Low-Density Lipoprotein by a Hypochlorous Acid- Dependent Mechanism: The Role of Vitamin C
  29. Perturbation of Lipid Metabolism by Linoleic Acid Hydroperoxide in CaCo-2 Cells
  30. Irreversible Thiol Oxidation in Carbonic Anhydrase III: Protection by S-Glutathiolation and Detection in Aging Rats
  31. Green Tea Extract Protects against Early Alcohol-Induced Liver Injury in Rats
  32. Comparing β-Carotene, Vitamin E and Nitric Oxide as Membrane Antioxidants
  33. Induction of Thioredoxin Reductase Gene Expression by Peroxynitrite in Human Umbilical Vein Endothelial Cells
  34. Activation of c-Jun N-Terminal Kinase and Apoptosis in Endothelial Cells Mediated by Endogenous Generation of Hydrogen Peroxide
  35. Detection of Poly(ADP-Ribose) by Immunocytochemistry: A Sensitive New Method for the Early Identification of UVB- and H2O2-Induced Apoptosis in Keratinocytes
  36. Efficacy of HOCl Scavenging by Sulfur- Containing Compounds: Antioxidant Activity of Glutathione Disulfide?
  37. Cysteine Supplementation Prevents Unweighting-Induced Ubiquitination in Association with Redox Regulation in Rat Skeletal Muscle
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