N-acetylcysteine, a cancer chemopreventive agent, causes oxidative damage to cellular and isolated DNA.
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 (H(2)O(2))-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 (32)P-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 H(2)O(2) 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 H(2)O(2) 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 H(2)O(2) 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.
Oikawa
S
S
Department of Hygiene, Mie University School of Medicine, Mie 514, Japan.
Yamada
K
K
Yamashita
N
N
Tada-Oikawa
S
S
Kawanishi
S
S
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000111:Acetylcysteine / Q000009:adverse effects*; D015415:Biomarkers; D003300:Copper / Q000494:pharmacology; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000009:adverse effects*; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D017422:Sequence Analysis, DNA; D014407:Tumor Cells, Cultured / Q000187:drug effects
D015415:Biomarkers; D016166:Free Radical Scavengers; D003300:Copper; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D003849:Deoxyguanosine; D000111:Acetylcysteine