Carcinogenesis, Vol. 22, No. 4, 627-634,
April 2001
© 2001 Oxford University Press
CARCINOGENESIS |
Oxidative damage and direct adducts in calf thymus DNA induced by the pentachlorophenol metabolites, tetrachlorohydroquinone and tetrachloro-1,4-benzoquinone
Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina, Chapel Hill, NC 27599-7400, USA
DNA damage induced by quinoid metabolites of pentachlorophenol (PCP), i.e. tetrachloro-1,4-benzoquinone (Cl4BQ) and tetrachlorohydroquinone (Cl4HQ), was investigated in calf thymus DNA. The 32P-post-labeling assay revealed four major and several minor adducts (3.5 adducts per 105 total nucleotides) that were produced in calf thymus DNA treated with Cl4BQ (5 mM). These DNA adducts were chemically stable even after conditions that induce thermal depurination and are unlikely to undergo depurination/depyrimidination to form apurinic/apyrimidinic (AP) sites. In addition, increases in 8-hydroxy-deoxyguanosine (8-HO-dG) (5 8-HO-dG per 105 nucleotides) and AP sites (0.5 AP sites per 105 nucleotides) were observed in Cl4BQ-modified calf thymus DNA. Further investigation indicated that in the presence of Cu(II) and NADPH, low concentrations of Cl4BQ (1 µM) induced a doubling of 8-HO-dG (10 8-HO-dG per 105 nucleotides) and dramatic increases in AP sites (20 AP sites per 105 nucleotides) and DNA single-strand breaks. The types of DNA damage induced by Cl4HQ plus Cu(II) were similar to those by Cl4BQ plus Cu(II) and NADPH, whereas catalase inhibited the formation of DNA damage. These data suggest that oxidative damage is causally involved in the formation of AP sites. Concentration-dependent increases in 8-HO-dG induced by Cl4HQ plus Cu(II) and Cl4BQ plus Cu(II) and NADPH were correlated with the formation of AP sites (r2 = 0.977) with a ratio of 8-HO-dG to AP sites at 1:1.6. The AP site-cleavage assay confirmed that ~85% of the AP sites induced by Cl4HQ and Cu(II) were detected as 5'-cleaved AP sites. Since hydrogen peroxide alone causes similar DNA damage, these results suggest the involvement of Cu(II) and hydrogen peroxide in the induction of oxidative DNA damage by Cl4HQ/Cl4BQ. The data demonstrate that PCP quinone and hydroquinone induce direct and oxidative base modifications as well as the formation of 5'-cleaved AP sites in genomic DNA. These lesions may have important implications for PCP clastogenicity and carcinogenicity.
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