Carcinogenesis, Vol. 20, No. 8, 1485-1490,
August 1999
© 1999 Oxford University Press
Molecular Epidemiology and Cancer Prevention |
N-acetylcysteine, a cancer chemopreventive agent, causes oxidative damage to cellular and isolated DNA
Department of Hygiene, Mie University School of Medicine, Mie 514, Japan
Although N-acetylcysteine is an antioxidant which has been expected to be a cancer chemopreventive agent, its safety and risk assessment have not been evaluated. N-acetylcysteine increased the amount of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a characteristic oxidative DNA lesion, in human leukemia cell line HL-60, whereas the amount of 8-oxodG in HP100, which is a hydrogen peroxide (H2O2)-resistant cell line derived from HL-60, was not increased. To clarify the mechanism of cellular DNA damage, we investigated DNA damage and its site specificity induced by N-acetylcysteine, using 32P-labeled DNA fragments obtained from the human p53 tumor suppressor gene and the c-Ha-ras-1 protooncogene. N-acetylcysteine induced extensive DNA damage in the presence of Cu(II). The DNA cleavage was enhanced by piperidine treatment, suggesting that N-acetylcysteine plus Cu(II) caused not only deoxyribose phosphate backbone breakage but also base modification. N-acetylcysteine plus Cu(II) frequently modified thymine and guanine residues. Bathocuproine, a specific Cu(I) chelator, and catalase inhibited the DNA damage, indicating the participation of Cu(I) and H2O2 in the DNA damage. Typical hydroxyl radical scavengers did not inhibit N-acetylcysteine plus Cu(II)-induced DNA damage, whereas methional completely inhibited it. These results suggest that reactive species derived from the reaction of H2O2 with Cu(I) participates in N-acetylcysteine plus Cu(II)-induced DNA damage. The content of 8-oxodG in calf thymus DNA was increased by N-acetylcysteine in the presence of Cu(II). The present study has demonstrated that N-acetylcysteine could induce metal-dependent H2O2 generation and, subsequently, damage to cellular and isolated DNA. Therefore, it is reasonable to consider that N-acetylcysteine may have the dual function of carcinogenic and anti-carcinogenic potentials. This work requires further studies on safety and risk assessment of N-acetylcysteine.
Abbreviations: 8-oxodG, 8-oxo-7,8-dihydro-2'-deoxyguanosine (and also known as 8-hydroxy-2'-deoxyguanosine); DTPA, diethylenetriamine-N,N,N',N'',N''-pentaacetic acid; SOD, superoxide dismutase; H2O2, hydrogen peroxide; HPLC–ECD, high pressure liquid chromatography with electrochemical detection; OH·, hydroxyl free radical
1 To whom correspondence should be addressed E-mail: kawanisi{at}doc.medic.mie-u.ac.jp
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