Journal Article

Site specificity and mechanism of oxidative DNA damage induced by carcinogenic catechol

Shinji Oikawa, Iwao Hirosawa, Kazutaka Hirakawa and Shosuke Kawanishi

in Carcinogenesis

Volume 22, issue 8, pages 1239-1245
Published in print August 2001 | ISSN: 0143-3334
Published online August 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.8.1239
Site specificity and mechanism of oxidative DNA damage induced by carcinogenic catechol

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Catechol, a naturally occurring and an important industrial chemical, has been shown to have strong promotion activity and induce glandular stomach tumors in rodents. In addition, catechol is a major metabolite of carcinogenic benzene. To clarify the carcinogenic mechanism of catechol, we investigated DNA damage using human cultured cell lines and 32P-labeled DNA fragments obtained from the human p53 and p16 tumor suppressor genes and the c-Ha-ras-1 proto-oncogene. Catechol increased the amount of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), which is known to be correlated with the incidence of cancer, in a human leukemia cell line HL-60, whereas the amount of 8-oxodG in its hydrogen peroxide (H2O2)-resistant clone HP100 was not increased. The formation of 8-oxodG in calf thymus DNA was increased by catechol in the presence of Cu2+. Catechol caused damage to 32P-labeled DNA fragments in the presence of Cu2+. When NADH was added, DNA damage was markedly enhanced and clearly observed at relatively low concentrations of catechol (<1 μM). DNA cleavage was enhanced by piperidine treatment, suggesting that catechol plus NADH caused not only deoxyribose phosphate backbone breakage but also base modification. Catechol plus NADH frequently modified thymine residues. Bathocuproine, a specific Cu+ chelator and catalase inhibited the DNA damage, indicating the participation of Cu+ and H2O2 in DNA damage. Typical hydroxyl radical scavengers did not inhibit catechol plus Cu2+-induced DNA damage, whereas methional completely inhibited it. These results suggest that reactive species derived from the reaction of H2O2 with Cu+ participates in catechol-induced DNA damage. Therefore, we conclude that oxidative DNA damage by catechol through the generation of H2O2 plays an important role in the carcinogenic process of catechol and benzene.

Keywords: 8-oxodG, 8-oxo-7,8-dihydro-2′-deoxyguanosine; DTPA, diethylenetriamine-N,N,N′,N′ ′,N′ ′-pentaacetic acid; H2O2, hydrogen peroxide; HPLC, high-performance liquid chromatography; HPLC–ECD, electrochemical detector coupled to HPLC; OH˙, free hydroxyl radical; O2˙–, superoxide anion radical; SOD, superoxide dismutase.

Journal Article.  5515 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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