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Nickel(II)- and Cobalt(II)-dependent Damage by Hydrogen Peroxide to the DNA Bases in Isolated Human Chromatin¹

Chemical Science and Technology Laboratory, National Institute of Standards and Technology, Gaithersburg, Maryland 20899 [Z. N., M. D.]; Department of Radiotherapy, University of Stellenbosch, Tygerberg, South Africa [Z. N.]; Chemical and Biochemical Engineering, University of Maryland Baltimore County and Medical Biotechnology Center, Maryland Biotechnology Institute, Baltimore, Maryland 21228 [G. R.]; Laboratory of Comparative Carcinogenesis, National Cancer Institute, FCRDC, Frederick, Maryland 21702 [K. S. K.]; and Pulmonary Medicine, University of California Davis Medical Center, Sacramento, California 95817 [B. H.]

Nickel compounds are known to be carcinogenic to humans and animals. Cobalt compounds produce tumors in animals and are probably carcinogenic to humans. The mechanisms of the carcinogenicity of these metal compounds, however, have remained elusive. In the present work, we have investigated the ability of Ni(II) and Co(II) ions in the presence of H₂O₂ to cause chemical changes in DNA bases in chromatin extracted from cultured cells of human origin. Eleven modified DNA bases in chromatin were identified and quantitated by the use of gas chromatography-mass spectrometry. 2-Hydroxyadenine (isoguanine), which has not previously been shown to occur in DNA or chromatin, was also identified. Products identified were typical hydroxyl radical-induced products of DNA bases, suggesting that the hydroxyl radical was involved in their formation. This idea was supported by partial inhibition of product formation by typical scavengers of hydroxyl radical. Partial inhibition of product formation indicated a possible "site-specific" formation of hydroxyl radical by unchelated Ni(II) and Co(II) ions bound to chromatin. Although treatment of chromatin for 1 h with Co(II)/H₂O₂ caused formation of significant amounts of products, treatment with Ni(II)/H₂O₂ required incubation times of more than 5 h and an increase in Ni(II) concentration before increases in product amounts above background levels became detectable. In both cases, ascorbic acid did not increase product yields. Glutathione at a physiologically relevant concentration had little overall effect on DNA base modification. Superoxide dismutase increased the yields of most products. Chelation of Ni(II) and Co(II) ions with EDTA almost completely inhibited product formation. Ni(II) in the presence of H₂O₂ produced greater base damage to the DNA in chromatin than to isolated DNA, unlike other metal ions tested. DNA damage in chromatin caused by Ni(II) and Co(II) ions in the presence of H₂O₂ may contribute to the established genotoxicity and carcinogenicity of these metal ions.

¹ This work was supported in part by the Office of Health and Environmental Research, Office of Energy Research, US Department of Energy, Washington, DC. Z. N. received support from the South African Medical Research Council. G. R. was supported by the National Science Foundation (EET-8808775). B. H. is the recipient of research support from the Medical Research Council and the Arthritis and Rheumatism Council, United Kingdom.

² Permanent address: Biochemistry Department, University of London King's College, Strand Campus, London WC2R 2LS, United Kingdom.

³ To whom requests for reprints should be addressed.

Received 5/23/91. Accepted 8/15/91.

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