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

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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 32 P-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 (H 2 O 2 )-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 32 P-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 (+ chelator and catalase inhibited the DNA damage, indicating the participation of Cu + and H 2 O 2 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 H 2 O 2 with Cu + participates in catechol-induced DNA damage. Therefore, we conclude that oxidative DNA damage by catechol through the generation of H 2 O 2 plays an important role in the carcinogenic process of catechol and benzene.

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