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

Abstract

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 Cu(2+). Catechol caused damage to 32P-labeled DNA fragments in the presence of Cu(2+). When NADH was added, DNA damage was markedly enhanced and clearly observed at relatively low concentrations of catechol (<1 microM). 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 Cu(2+)-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.

Two-Electron Quinone Reductase (Aldo-keto Reductase 1C Isozyme) Augments the Oxidative DNA Damage Induced by Quinones in Diesel Exhaust Particles by Accelerating Redox Cycling

“…[12][13][14][15][16][17][18][19][20] Consistent with this notion, we also detected ROS and Cu(I) in the reaction mixture that caused DNA damage. To clarify the active species responsible for the DNA damage, the effects of ROS scavengers and a Cu(I)-specific chelator were examined.…”

“…Taken together, these results also suggest that Cu(I)-OOH complexes derived from the reaction of hydrogen peroxide with Cu(I) may play a role in causing DNA damage, as proposed by Kawanishi and co-workers. 13) The Cu(I) formed from Cu(II) bound to DNA interacts with hydrogen peroxide, resulting in the formation of DNA-Cu(I)-OOH complexes. Hydroxyl radicals released from these complexes immediately attack adjacent DNA before they can be scavenged by hydroxyl radicals scavengers.…”

“…11) Oxidative DNA damage induced by catechols and quinones has been studied extensively to understand their toxicity. [12][13][14][15][16][17][18][19][20] Catechol and 1,4-hydroquinone (metabolites of benzene), [12][13][14] catechol estrogen 15,16) and dopa 17) were reported to induce DNA damage in the presence of transition metals, especially Cu, and this DNA damage was enhanced by NADH. Quinones such as 1,2-naphthoquinone (1,2-NQ) and benzo[a]pyrene-7,8-dione were also found to be able to cause oxidative DNA damage in the presence of both NADPH and Cu(II).…”

Sequence-specific DNA damage by reactive oxygen species: Implications for carcinogenesis and aging

“…Interestingly, the ROS can be produced abundantly through the reduction of the oxidized form, such as semiquinone radical or 1,2-benzoquinone, by NADH non-enzymatically. Collectively, it is concluded that the oxidative DNA damage by catechol through generation of ROS plays an important role in the carcinogenic process of catechol and benzene (24,25).…”

Chemiluminescence assay for quinones based on generation of reactive oxygen species through the redox cycle of quinone

“…The CL time profiles were apparently different between these structural isomers. It has been reported that p-quinone is reduced to semiquinone radical by singleelectron reduction [31] whereas o-quinone is reduced to quinol by two-electron reduction [29,32] The CL of the biologically important quinones such as ubiquinone, phylloquinone and PQQ was also measured by the proposed CL assay and the intense CLs were observed for these quinones. …”