title: Furazolidone induced oxidative DNA damage via up-regulating ROS that caused cell cycle arrest in human hepatoma G2 cells.
abstract: Furazolidone (FZD) is an antimicrobial agent that has been shown to have mutagenic, genotoxic and potentially carcinogenic properties when tested in a variety of systems in vitro and in vivo. In this study, we investigated FZD's DNA damaging effect in human hepatoma cells aiming at further defining the molecular mechanism of FZD's cytotoxicity. Addition of FZD resulted in cell growth suppression and cell cycle arrest in S phase accompanied by remarkable DNA strand breaks with increased levels of intracellular reactive oxygen species (ROS) and 8-hydroxydeoxyguanosine. Activities of antioxidases were down-regulated following FZD treatment and antioxidant agent catalase and superoxide dismutase ameliorated FZD's DNA damaging effects. Moreover, FZD caused much more extensive damage to mitochondrial DNA (mtDNA) than to nuclear DNA for which the decrease in mtDNA content correlated with FZD usage in a dose-dependent manner. However, there was no evidence of FZD induced mtDNA mutation in the mitochondrial DNA displacement loop. These results demonstrate that FZD up-regulates the production of intracellular ROS to cause oxidative DNA damage with mtDNA being the most vulnerable targets. Oxidative stress and the injury of mtDNA could be early indicators of FZD-induced cytotoxicity, with the resulting abnormal progression of the cell cycle.
authors.affiliation: Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Jin
authors.forename: Shusheng
authors.initials: S
authors.lastname: Tang
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Jiajie
authors.initials: J
authors.lastname: Zou
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Fengying
authors.initials: F
authors.lastname: Liu
authors.forename: Shen
authors.initials: S
authors.lastname: Zhang
authors.forename: Chundi
authors.initials: C
authors.lastname: Sun
authors.forename: Xilong
authors.initials: X
authors.lastname: Xiao
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000891:Anti-Infective Agents, Local / Q000633:toxicity*; D000975:Antioxidants / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005664:Furazolidone / Q000633:toxicity*; D006801:Humans; D009154:Mutation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D000891:Anti-Infective Agents, Local; D000975:Antioxidants; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D005664:Furazolidone; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine