© 1995 Oxford University Press
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Urinary and urothelial effects of sodium salts in male rats
Department of Pathology and Microbiology and Eppley Institute for Research on Cancer, University of Nebraska Medical Center 600 South 42nd Street, Omaha, NE 68198–3135, USA
The oxidative DNA damage induced by the renal carcinogen potassium bromate (KBrO3) in cultured mammalian cells and in a cell-free system was characterized by means of various repair endonucleases. Under cell-free conditions, no modifications were induced by KBrO3 alone, but extensive DNA damage was observed in the presence of glutathione (GSH). The DNA damage was found to consist mostly of base modifications sensitive to Fpg protein (formamidopyrimidine-DNA glycosylase). HPLC analysis demonstrated that many of the modifications were 7,8-dihydro-8-oxoguanine (8-hydroxyguanine) residues. Single-strand breaks, sites of base loss (AP sites) and base modifications sensitive to endonuclease III (5,6-dihydropyrimidine derivatives) were formed in only low amounts. This ‘damage profile’ and experiments with various scavengers (catalase, superoxide dismutase, deferoxamine, azide, tert-butanol) and D2O as solvent excluded the involvement of hydroxyl radicals and singlet oxygen in the damage production, but were consistent with a radical mechanism involving bromine radicals. In L1210 mouse leukemia cells and LLC-PK1 porcine kidney cells, KBrO3 alone gave rise to a DNA damage profile similar to that observed after treatment of cell-free DNA with KBrO3 plus GSH, i.e. base modifications sensitive to Fpg protein were formed in high excess of all other lesions quantified. In LLC-PK1 cells (derived from the target organ of KBrO3 carcinogenesis) the level of DNA damage was twice that in the L1210 cells. DNA damage was partially prevented by depletion of intracellular GSH with diethylmaleate, indicating that GSH played an activating role in the cells similar to that seen under cell-free conditions. The Fpg-sensitive base modifications induced by KBrO3 were repaired with only moderate efficiency (38 ± 10% of the lesions were still present after 18 h in full medium) under conditions that did not influence cell proliferation.
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