Details

Autor(en) / Beteiligte

• Murata, Mariko
• Tezuka, Taro
• Ohnishi, Shiho
• Takamura-Enya, Takeji
• Hisamatsu, Yoshiharu
• Kawanishi, Shosuke

Titel

Carcinogenic 3-nitrobenzanthrone induces oxidative damage to isolated and cellular DNA

Ist Teil von

• Free radical biology & medicine, 2006-04, Vol.40 (7), p.1242-1249

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2006

Quelle

MEDLINE

Beschreibungen/Notizen

• 3-Nitrobenzanthrone (3-NBA) is an extremely potent mutagen in diesel exhaust. It is a lung carcinogen to rats, and therefore a suspected carcinogen to human. In order to clarify the mechanism of carcinogenicity of 3-NBA, we investigated oxidative DNA damage by N-hydroxy-3-aminobenzanthrone (N-OH-ABA), a metabolite of 3-NBA, using 32P-labeled DNA fragments from the human p53 tumor-suppressor gene. N-OH-ABA caused Cu(II)-mediated DNA damage, and endogenous reductant NADH dramatically enhanced this process. Catalase and a Cu(I)-specific chelator decreased DNA damage, suggesting the involvement of hydrogen peroxide (H 2O 2) and Cu(I). N-OH-ABA induced DNA damage at cytosine and guanine residues of ACG sequence complementary to codon 273, a well-known hot spot of the p53 gene. N-OH-ABA dose dependently induced 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) formation in the presence of Cu(II) and NADH. Treatment with N-OH-ABA increased amounts of 8-oxodG in HL-60 cells compared to the H 2O 2-resistant clone HP100, supporting the involvement of H 2O 2. The present study has demonstrated that the N-hydroxy metabolite of 3-NBA induces oxidative DNA damage through H 2O 2 in both a cell-free system and cultured human cells. We conclude that oxidative DNA damage may play an important role in the carcinogenic process of 3-NBA in addition to previously reported DNA adduct formation.