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J Biol Chem, Vol. 274, Issue 30, 20909-20915, July 23, 1999

Cytotoxicity and Site-specific DNA Damage Induced by Nitroxyl Anion (NO) in the Presence of Hydrogen Peroxide
IMPLICATIONS FOR VARIOUS PATHOPHYSIOLOGICAL CONDITIONS

Laurence Chazotte-Aubert, Shinji Oikawa^§, Isabelle Gilibert, Franca Bianchini, Shosuke Kawanishi^§, and Hiroshi Ohshima

From the  Unit of Endogenous Cancer Risk Factors, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France and the ^§ Department of Hygiene, Mie University School of Medicine, Mie 514, Japan

Nitroxyl anion (NO), the one-electron reduction product of nitric oxide (NO^·), is formed under various physiological conditions. We have used four different assays (DNA strand breakage, 8-oxo-deoxyguanosine formation in calf thymus DNA, malondialdehyde generation from 2'-deoxyribose, and analysis of site-specific DNA damage using ³²P-5'-end-labeled DNA fragments of the human p53 tumor suppressor gene and the c-Ha-ras-1 protooncogene) to study the effects of NO generated from Angeli's salt on DNA damage. It was found that strong oxidants are generated from NO, especially in the presence of H₂O₂ plus Fe(III)-EDTA or Cu(II). NO^· released from diethylamine-NONOate had no such effect. Distinct effects of hydroxyl radical (HO^·) scavengers and patterns of site-specific DNA cleavage caused by Angeli's salt alone or by Angeli's salt, H₂O₂ plus metal ion suggest that NO acts as a reductant to catalyze the formation of the HO^· from H₂O₂ plus Fe(III) and formation of Cu(I)-peroxide complexes with a reactivity similar to HO^· from H₂O₂ and Cu(II). Angeli's salt and H₂O₂ exerted synergistically cytotoxic effects to MCF-7 cells, determined by lactate dehydrogenase release assay. Thus NO may play an important role in the etiology of various pathophysiological conditions such as inflammation and neurodegenerative diseases, especially when H₂O₂ and transition metallic ions are present.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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