Abstract
Homocysteine is considered to be an important risk factor for cancer as well as cardiovascular diseases. To clarify whether homocysteine has potential carcinogenicity, we investigated formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), which is known to be correlated with the incidence of cancer, induced by homocysteine in human cultured cell lines. Homocysteine increased the amount of 8-oxodG in human leukemia cell line HL-60, whereas the amount of 8-oxodG in its hydrogen peroxide (H2O2)-resistant clone HP100 was not increased. We investigated the mechanism for oxidative DNA damage by homocysteine using 32P-labeled DNA fragments obtained from human tumor suppressor genes and a proto-oncogene. There were two mechanisms by which homocysteine caused DNA damage in the presence of Cu(II). A low concentration of homocysteine (20 μ M) frequently induced piperidine-labile sites at thymine residues, whereas a high concentration of homocysteine (100 μ M) resulted in damage principally to guanine residues. Catalase inhibited DNA damage by 20 μ M homocysteine, indicating the participation of H2O2, but was ineffective in preventing DNA damage by 100 μ M homocysteine. Experiments using a singlet oxygen probe showed that 100 μ M homocysteine enhanced chemiluminescence intensity in deuterium oxide more than that in H2O. These results indicated that the metal-dependent DNA damage through H2O2 is likely to be a more relevant mechanism for homocysteine carcinogenicity.
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Abbreviations
- 8-oxodG:
-
8-oxo-7,8-dihydro-2′-deoxyguanosine
- DTPA:
-
diethylenetriamine-N,N,N′,N″,N″-pentaacetic acid
- SOD:
-
superoxide dismutase
- H2O2:
-
hydrogen peroxide
- HPLC:
-
high-performance liquid chromatography
- HPLC-ECD:
-
electrochemical detector coupled to HPLC
- •OH:
-
hydroxyl free radical
- O2−:
-
superoxide anion
- MVP:
-
trans-1-(2′-methoxyvinyl)pyrene
- 1O2:
-
singlet oxygen
- D2O:
-
deuterium oxide
- MTHFR:
-
methylenetetrahydrofolate reductase gene
- DABCO:
-
1,4-diazabicyclo[2,2,2]-octane
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This work was supported by a Grant-in-Aid from the Ministry of Education, Science, Sports, and Culture of Japan.
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Oikawa, S., Murakami, K. & Kawanishi, S. Oxidative damage to cellular and isolated DNA by homocysteine: implications for carcinogenesis. Oncogene 22, 3530–3538 (2003). https://doi.org/10.1038/sj.onc.1206440
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DOI: https://doi.org/10.1038/sj.onc.1206440
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