Mitochondrial DNA Damage during Mitochondrial Lipid Peroxidation
It is well known that the carcinogenic potency of radiation and chemical carcinogens is closely correlated with the induction of DNA damage (1–3); however, the ultimate mechanisms involved are far from clear. In the case of high energy radiation, generation of hydroxyl radicals (OH·) probably plays a key role, either by direct attack of OH· on DNA, or indirectly via initiation of lipid peroxidation (4,5). Initiation of lipid peroxidation may also be a consequence of the generation of oxygen centered radicals in the oxidative stress associated with metabolism of some chemical carcinogens(6). Thus lipid peroxidation may be one of the mechanisms linking both radiation and metabolism of chemical carcinogens to DNA damage. This view is supported by reports (7–12) that products of lipid peroxidation can cause DNA damage in model systems and mutations in prokaryotes. However, actual data showing DNA damage to eukaryotic genes by lipid peroxidation is limited and indirect (5,13). In this communication, evidence is reported showing extensive damage to DNA of liver mitochondria occurring concomitantly with mitochondrial lipid peroxidation. Mitochondrial rather than nuclear DNA was studied since the former exists as a discrete circular molecule of single molecular weight, which facilitates detection of small degrees of DNA damage. The study of the relationship between lipid peroxidation and DNA damage in mitochondria is important in the assessment of the carcinogenic potency of oxidative stress, especially since many strong carcinogenic agents preferentially attack mitochondrial DNA (14).
KeywordsLipid Peroxidation Chemical Carcinogen Malonic Dialdehyde High Energy Radiation Carcinogenic Potency
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- 1.D. Grunberger and R.M. Santella, Conformational changes in DNA induced by chemical carcinogens. In Genes and Proteins in Oncogenesis (I. B. Weinstein and H. J. Vogel, Eds.) pp. 13–40. Academic Press, New York (1983).Google Scholar
- 2.I. Emerit and P. Cerutti, Icosanoids and chromosome damage. In Icosanoids and Cancer (H. Thaler-Dao, A. Crastes de Paulet and R. Paoletti, Eds.) pp. 127–138. Raven Press, New York (1984).Google Scholar
- 3.R. L. Willson, Iron and hydroxyl free radicals in enzyme inactivation and cancer. In Free Radicals, Lipid Peroxidation and Cancer (D.C.H. McBrien and T.F. Slater, Eds.) pp. 275–303. Academic Press, New York (1982).Google Scholar
- 4.M.G. Simic and S.V. Jovanovic, Free radical mechanisms of DNA base damage. In Mechanisms of DNA Damage and Repair (M.G. Simic, L. Grossman and A.C. Upton, Eds.) pp. 39–49. Plenum Press, New York (1986).Google Scholar
- 7.U. Reiss and A.L. Tappel, Fluorescent product formation and changes in structure of DNA reacted with peroxidizing arachidonic acid. Lipids J, 199–202 (1973).Google Scholar
- 8.S. Yonei and H. Furui, Lethal and mutagenic effects of malondialdehyde, a decomposition product of peroxidized lipids, on Escherichia coli with different DNA-repair capacities. Mutation Res. 23–32 (1981).Google Scholar
- 12.S. Alaska, Inactivation of transforming activity of plasmid DNA by lipid peroxidation. Biochim. Biophys. Acta, 867, 201–208 (1986).Google Scholar
- 13.I. Emerit, S.H. Khan and P.A. Cerutti, Treatment of lymphocyte cultures with a hypoxanthine-xanthine oxidase system induces the formation of transferable clastogenic material. J. Free Rad. Biol. Med. U 51–57 (1985).Google Scholar
- 16.O.H. Lowry, N.J. Rosebrough, A.L. Farr and R.J. Randall, Protein measurement with the folin phenol reagent. J. of Biol. Chem. 193, 265–275 (1951).Google Scholar
- J. F. Francisco, F.F. Vissering and M.V. Simpson, Two aspects of mitochondrial DNA structure: The occurrence of two types of mitochondrial DNA in rat liver and the isolation from rat liver of DNA complexes of high buoyant density. In Mitochondria 1977 (W. Bendlow, R.J. Schueyen, K. Wolf and K. Kardewitz, Eds.) pp. 25–37. Walter de Gruyter, New York.Google Scholar
- A.M. Hruszkewycz (unpublished results).Google Scholar