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Oxidative DNA damage and apoptosis induced by benzene metabolites



Oxidative DNA damage and apoptosis induced by benzene metabolites



Cancer Research 56(22): 5172-5178



Benzene is a widely recognized human carcinogen. The mechanism of DNA damage induced by major benzene metabolites 1,4-benzoquinone (1,4-BQ) and hydroquinone (1,4-HQ) was investigated in relation to apoptosis and carcinogenesis. Pulsed-field gel electrophoresis showed that cellular DNA strand breakage was induced by benzene metabolites. Internucleosomal DNA fragmentation and morphological changes of apoptotic cells were observed at higher concentrations of benzene metabolites. Flow cytometry showed an increase of peroxides in cultured cells treated with benzene metabolites. 1,4-BQ induced these changes at a much lower concentration than 1,4-HQ. Damage to DNA fragments obtained from the c-Ha-ras-1 proto-oncogene was investigated by a DNA sequencing technique. 1,4-BQ + NADH and 1,4-HQ induced piperidine-labile sites frequently at thymine residues in the presence of Cu(II). Catalase and bathocuproine inhibited DNA damage, suggesting that H-2O-2 reacts with Cu(I) to produce active species causing DNA damage. Electron spin resonance studies showed that semiquinone radical was produced by NADH-mediated reduction of 1,4-BQ and autoxidation of 1,4-HQ, suggesting that benzene metabolites produce O-2- and H-2O-2 via the formation of semiquinone radical. These results suggest that these benzene metabolites cause DNA damage through H-20-2 generation in cells, preceding internucleosomal DNA fragmentation leading to apoptosis. The fates of the cells to apoptosis or mutation might be dependent on the intensity of DNA damage and the ability to repair DNA.

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Accession: 009147107

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PMID: 8912853


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