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. 1990 Jun;87(12):4533–4537. doi: 10.1073/pnas.87.12.4533

Oxidative damage to DNA during aging: 8-hydroxy-2'-deoxyguanosine in rat organ DNA and urine.

C G Fraga 1, M K Shigenaga 1, J W Park 1, P Degan 1, B N Ames 1
PMCID: PMC54150  PMID: 2352934

Abstract

Oxidative damage to DNA is shown to be extensive and could be a major cause of the physiological changes associated with aging and the degenerative diseases related to aging such as cancer. The oxidized nucleoside, 8-hydroxy-2'-deoxyguanosine (oh8dG), one of the approximately 20 known oxidative DNA damage products, has been measured in DNA isolated from various organs of Fischer 344 rats of different ages. oh8dG was present in the DNA isolated from all the organs studied: liver, brain, kidney, intestine, and testes. Steady-state levels of oh8dG ranged from 8 to 73 residues per 10(6) deoxyguanosine residues or 0.2-2.0 x 10(5) residues per cell. Levels of oh8dG in DNA increased with age in liver, kidney, and intestine but remained unchanged in brain and testes. The urinary excretion of oh8dG, which presumably reflects its repair from DNA by nuclease activity, decreased with age from 481 to 165 pmol per kg of body weight per day for urine obtained from 2-month- and 25-month-old rats, respectively. 8-Hydroxyguanine, the proposed repair product of a glycosylase activity, was also assayed in the urine. We estimate approximately 9 x 10(4) oxidative hits to DNA per cell per day in the rat. The results suggest that the age-dependent accumulation of oh8dG residues observed in DNA from liver, kidney, and intestine is principally due to the slow loss of DNA nuclease activity; however, an increase in the rate of oxidative DNA damage cannot be ruled out.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adelman R., Saul R. L., Ames B. N. Oxidative damage to DNA: relation to species metabolic rate and life span. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2706–2708. doi: 10.1073/pnas.85.8.2706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ames B. N. Dietary carcinogens and anticarcinogens. Oxygen radicals and degenerative diseases. Science. 1983 Sep 23;221(4617):1256–1264. doi: 10.1126/science.6351251. [DOI] [PubMed] [Google Scholar]
  3. Ames B. N. Endogenous oxidative DNA damage, aging, and cancer. Free Radic Res Commun. 1989;7(3-6):121–128. doi: 10.3109/10715768909087933. [DOI] [PubMed] [Google Scholar]
  4. Babior B. M. Oxidants from phagocytes: agents of defense and destruction. Blood. 1984 Nov;64(5):959–966. [PubMed] [Google Scholar]
  5. Cand F., Verdetti J. Superoxide dismutase, glutathione peroxidase, catalase, and lipid peroxidation in the major organs of the aging rats. Free Radic Biol Med. 1989;7(1):59–63. doi: 10.1016/0891-5849(89)90101-9. [DOI] [PubMed] [Google Scholar]
  6. Cathcart R., Schwiers E., Saul R. L., Ames B. N. Thymine glycol and thymidine glycol in human and rat urine: a possible assay for oxidative DNA damage. Proc Natl Acad Sci U S A. 1984 Sep;81(18):5633–5637. doi: 10.1073/pnas.81.18.5633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chance B., Sies H., Boveris A. Hydroperoxide metabolism in mammalian organs. Physiol Rev. 1979 Jul;59(3):527–605. doi: 10.1152/physrev.1979.59.3.527. [DOI] [PubMed] [Google Scholar]
  8. Dillard C. J., Tappel A. L. Fluorescent damage products of lipid peroxidation. Methods Enzymol. 1984;105:337–341. doi: 10.1016/s0076-6879(84)05044-8. [DOI] [PubMed] [Google Scholar]
  9. Dizdaroglu M. Formation of an 8-hydroxyguanine moiety in deoxyribonucleic acid on gamma-irradiation in aqueous solution. Biochemistry. 1985 Jul 30;24(16):4476–4481. doi: 10.1021/bi00337a032. [DOI] [PubMed] [Google Scholar]
  10. Floyd R. A., West M. S., Eneff K. L., Hogsett W. E., Tingey D. T. Hydroxyl free radical mediated formation of 8-hydroxyguanine in isolated DNA. Arch Biochem Biophys. 1988 Apr;262(1):266–272. doi: 10.1016/0003-9861(88)90188-9. [DOI] [PubMed] [Google Scholar]
  11. Fraga C. G., Arias R. F., Llesuy S. F., Koch O. R., Boveris A. Effect of vitamin E- and selenium-deficiency on rat liver chemiluminescence. Biochem J. 1987 Mar 1;242(2):383–386. doi: 10.1042/bj2420383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fridovich I., Freeman B. Antioxidant defenses in the lung. Annu Rev Physiol. 1986;48:693–702. doi: 10.1146/annurev.ph.48.030186.003401. [DOI] [PubMed] [Google Scholar]
  13. Gupta R. C. Nonrandom binding of the carcinogen N-hydroxy-2-acetylaminofluorene to repetitive sequences of rat liver DNA in vivo. Proc Natl Acad Sci U S A. 1984 Nov;81(22):6943–6947. doi: 10.1073/pnas.81.22.6943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Harman D. The aging process. Proc Natl Acad Sci U S A. 1981 Nov;78(11):7124–7128. doi: 10.1073/pnas.78.11.7124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Holliday R. The inheritance of epigenetic defects. Science. 1987 Oct 9;238(4824):163–170. doi: 10.1126/science.3310230. [DOI] [PubMed] [Google Scholar]
  16. Jamieson D., Chance B., Cadenas E., Boveris A. The relation of free radical production to hyperoxia. Annu Rev Physiol. 1986;48:703–719. doi: 10.1146/annurev.ph.48.030186.003415. [DOI] [PubMed] [Google Scholar]
  17. Kasai H., Crain P. F., Kuchino Y., Nishimura S., Ootsuyama A., Tanooka H. Formation of 8-hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repair. Carcinogenesis. 1986 Nov;7(11):1849–1851. doi: 10.1093/carcin/7.11.1849. [DOI] [PubMed] [Google Scholar]
  18. Kasai H., Nishimura S. Hydroxylation of deoxyguanosine at the C-8 position by ascorbic acid and other reducing agents. Nucleic Acids Res. 1984 Feb 24;12(4):2137–2145. doi: 10.1093/nar/12.4.2137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kasai H., Nishimura S., Kurokawa Y., Hayashi Y. Oral administration of the renal carcinogen, potassium bromate, specifically produces 8-hydroxydeoxyguanosine in rat target organ DNA. Carcinogenesis. 1987 Dec;8(12):1959–1961. doi: 10.1093/carcin/8.12.1959. [DOI] [PubMed] [Google Scholar]
  20. Kirkwood T. B. DNA, mutations and aging. Mutat Res. 1989 Jan;219(1):1–7. doi: 10.1016/0921-8734(89)90035-0. [DOI] [PubMed] [Google Scholar]
  21. Kuchino Y., Mori F., Kasai H., Inoue H., Iwai S., Miura K., Ohtsuka E., Nishimura S. Misreading of DNA templates containing 8-hydroxydeoxyguanosine at the modified base and at adjacent residues. Nature. 1987 May 7;327(6117):77–79. doi: 10.1038/327077a0. [DOI] [PubMed] [Google Scholar]
  22. Loeb L. A. Endogenous carcinogenesis: molecular oncology into the twenty-first century--presidential address. Cancer Res. 1989 Oct 15;49(20):5489–5496. [PubMed] [Google Scholar]
  23. Masoro E. J., Yu B. P., Bertrand H. A. Action of food restriction in delaying the aging process. Proc Natl Acad Sci U S A. 1982 Jul;79(13):4239–4241. doi: 10.1073/pnas.79.13.4239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nakatsuru Y., Aoki K., Ishikawa T. Age and strain dependence of O6-methylguanine DNA methyltransferase activity in mice. Mutat Res. 1989 Jan;219(1):51–56. doi: 10.1016/0921-8734(89)90040-4. [DOI] [PubMed] [Google Scholar]
  25. Oliver C. N., Ahn B. W., Moerman E. J., Goldstein S., Stadtman E. R. Age-related changes in oxidized proteins. J Biol Chem. 1987 Apr 25;262(12):5488–5491. [PubMed] [Google Scholar]
  26. Park J. W., Ames B. N. 7-Methylguanine adducts in DNA are normally present at high levels and increase on aging: analysis by HPLC with electrochemical detection. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7467–7470. doi: 10.1073/pnas.85.20.7467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Pryor W. A. Oxy-radicals and related species: their formation, lifetimes, and reactions. Annu Rev Physiol. 1986;48:657–667. doi: 10.1146/annurev.ph.48.030186.003301. [DOI] [PubMed] [Google Scholar]
  28. Randerath K., Reddy M. V., Disher R. M. Age- and tissue-related DNA modifications in untreated rats: detection by 32P-postlabeling assay and possible significance for spontaneous tumor induction and aging. Carcinogenesis. 1986 Sep;7(9):1615–1617. doi: 10.1093/carcin/7.9.1615. [DOI] [PubMed] [Google Scholar]
  29. Richter C., Park J. W., Ames B. N. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6465–6467. doi: 10.1073/pnas.85.17.6465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Shigenaga M. K., Gimeno C. J., Ames B. N. Urinary 8-hydroxy-2'-deoxyguanosine as a biological marker of in vivo oxidative DNA damage. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9697–9701. doi: 10.1073/pnas.86.24.9697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Summerfield F. W., Tappel A. L. Effects of dietary polyunsaturated fats and vitamin E on aging and peroxidative damage to DNA. Arch Biochem Biophys. 1984 Sep;233(2):408–416. doi: 10.1016/0003-9861(84)90462-4. [DOI] [PubMed] [Google Scholar]
  32. Tappel A. L. Lipid peroxidation damage to cell components. Fed Proc. 1973 Aug;32(8):1870–1874. [PubMed] [Google Scholar]
  33. Totter J. R. Spontaneous cancer and its possible relationship to oxygen metabolism. Proc Natl Acad Sci U S A. 1980 Apr;77(4):1763–1767. doi: 10.1073/pnas.77.4.1763. [DOI] [PMC free article] [PubMed] [Google Scholar]

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