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Mutation research

Role of active oxygen species in DNA damage by pentachlorophenol metabolites.


PMID 7523887

Abstract

Pentachlorophenol (PCP) has been shown to be carcinogenic for mice, although it does not seem to be mutagenic in bacterial test systems. In this study, the mechanism of DNA damage by PCP metabolites in the presence of metals was investigated with a DNA sequencing technique using 32P-labeled DNA fragments and with an electrochemical detector coupled to an HPLC. The metabolite tetrachlorohydroquinone (TCHQ) caused DNA damage in the presence of Cu(II) but not in the presence of either Mn(II) or Fe(III). TCHQ plus Cu(II) frequently induced piperidine-labile sites at thymine residues and guanine residues. The most preferred sites were the thymine residues of the 5'-GTC-3' sequence. TCHQ increased 8-oxo-7,8-dihydro-2'-deoxyguanosine in calf thymus DNA in the presence of Cu(II). Typical OH scavengers showed no inhibitory effects on TCHQ- plus Cu(II)-induced DNA damage. Bathocuproine and catalase inhibited DNA damage, suggesting that Cu(I) and H2O2 have important roles in the production of active species causing DNA damage. Tetrachloro-p-benzoquinone (TCBQ) alone did not induce DNA damage in the presence of Cu(II), but addition of NADH induced DNA cleavage even in the absence of NADH-FMN oxidoreductase. UV-visible and ESR spectroscopies have demonstrated that TCHQ is rapidly autoxidized into semiquinone even in the absence of metal ions, indicating that the semiquinone radical itself is not the main active species inducing DNA damage. These results suggest that the semiquinone radical produced by the autoxidation of TCHQ and/or the reduction of TCBQ by NADH reacts with dioxygen to form superoxide and subsequently H2O2, which is activated by transition metals to cause DNA damage.