Human DNA damage induced by 1,2,4-benzenetriol, a benzene metabolite.
Reactivities of benzene metabolites (phenol, catechol, hydroquinone, 1,4-benzoquinone, 1,2,4-benzenetriol) and related polyphenols (resorcinol, pyrogallol, phloroglucinol) with DNA were investigated by a DNA sequencing technique using 32P 5'-end-labeled DNA fragments obtained from human c-Ha-ras-1 protooncogene, and the reaction mechanism was studied by UV-visible and electron-spin resonance spectroscopies. 1,2,4-Benzenetriol caused strong DNA damage even without alkali treatment. Alkali-labile sites induced by 1,2,4-benzenetriol were base residues of guanine and adjacent thymine. Catalase, superoxide dismutase and methional inhibited the DNA damage completely, but sodium formate did not inhibit it. 1,2,4-Benzenetriol-induced DNA damage was inhibited by the addition of a Cu(I)-specific chelating agent, bathocuproine, and was accelerated by the addition of Cu(II). The addition of Fe(III) did not create any significant effects on 1,2,4-benzenetriol-induced DNA damage. Electron-spin resonance studies using spin traps demonstrated that addition of Fe(III) increased hydroxyl radical production during the autoxidation of 1,2,4-benzenetriol, whereas the addition of Cu(II) did not. The results suggest that DNA damage was caused by an unidentified active species which was produced by the autoxidation of 1,2,4-benzenetriol in the presence of Cu(II), rather than by hydroxyl radicals. The possibility that 1,2,4-benzenetriol-induced DNA damage is one of the primary reactions in carcinogenesis induced by benzene is discussed.
Kawanishi
S
S
Department of Public Health, Faculty of Medicine, Kyoto University, Japan.
Inoue
S
S
Kawanishi
M
M
D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D005609:Free Radicals; D006801:Humans; D006873:Hydroquinones / Q000633:toxicity*; D010084:Oxidation-Reduction; D013057:Spectrum Analysis
D002614:Chelating Agents; D005609:Free Radicals; D006873:Hydroquinones; C013038:hydroxyhydroquinone; D003300:Copper; D004247:DNA