title: Oxidative DNA damage induced by metabolites of chloramphenicol, an antibiotic drug.
abstract: Chloramphenicol (CAP) was an old antimicrobial agent. However, the use of CAP is limited because of its harmful side effects, such as leukemia. The molecular mechanism through which CAP has been strongly correlated with leukemogenesis is still unclear. To elucidate the mechanism of genotoxicity, we examined DNA damage by CAP and its metabolites, nitroso-CAP (CAP-NO), N-hydroxy-CAP (CAP-NHOH), using isolated DNA. CAP-NHOH have the ability of DNA damage including 8-oxo-7,8-dihydro-2'-deoxyguanosine formation in the presence of Cu(II), which was greatly enhanced by the addition of an endogenous reductant NADH. CAP-NO caused DNA damage in the presence of Cu(II), only when reduced by NADH. NADH can non-enzymatically reduce the nitroso form to hydronitroxide radicals, resulting in enhanced generation of reactive oxygen species followed by DNA damage through the redox cycle. Furthermore, we also studied the site specificity of base lesions in DNA treated with piperidine or formamidopyrimidine-DNA glycosylase, using (32)P-5'-end-labeled DNA fragments obtained from the human tumor suppressor gene. CAP metabolites preferentially caused double base lesion, the G and C of the ACG sequence complementary to codon 273 of the p53 gene, in the presence of NADH and Cu(II). Therefore, we conclude that oxidative double base lesion may play a role in carcinogenicity of CAP.
authors.affiliation: Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science , Suzuka, Mie , Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Ohnishi
authors.forename: Mariko
authors.initials: M
authors.lastname: Murata
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Ida
authors.forename: Shinji
authors.initials: S
authors.lastname: Oikawa
authors.forename: Shosuke
authors.initials: S
authors.lastname: Kawanishi
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D002417:Cattle; D002701:Chloramphenicol / Q000031:analogs & derivatives / Q000737:chemistry*; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D043382:DNA-Formamidopyrimidine Glycosylase / Q000737:chemistry; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000737:chemistry; D005609:Free Radicals / Q000737:chemistry; D016158:Genes, p53; D006801:Humans; D006878:Hydroxides; D006898:Hydroxylamines / Q000737:chemistry; D007938:Leukemia / Q000188:drug therapy; D010100:Oxygen / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D013950:Thymus Gland / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D005609:Free Radicals; D006878:Hydroxides; D006898:Hydroxylamines; C000607738:N-hydroxychloramphenicol; D010880:Piperidines; D017382:Reactive Oxygen Species; D002701:Chloramphenicol; C026099:nitrosochloramphenicol; C032727:piperidine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D043382:DNA-Formamidopyrimidine Glycosylase; D003849:Deoxyguanosine; D010100:Oxygen
keywords: 8-hydroxy-2′-deoxyguanosine; 8-oxodG; DNA oxidation; carcinogenesis; copper