Different cytoprotective effect of antioxidants and change in the iron regulatory system in rodent cells exposed to paraquat or formaldehyde.
To study the mechanism of toxicity of paraquat and formaldehyde, the response of oxidant-exposed cultured NIH3T3 cells to antioxidants or an iron chelator was investigated. Paraquat-induced cell death was reduced by treatment with 10 microM pyrrolidine dithiocarbamate (PDTC) and 10 microM desferrioxamine (DFO), but not with N-acetyl-L-cysteine (NAC). Cells were protected from formaldehyde-induced cytotoxicity by 1 mM NAC, but not by PDTC or DFO. Moreover, paraquat modulated the cellular iron regulatory system. Paraquat induced a time-dependent increase in the binding of iron regulatory protein 1 (IRP1) to iron-responsive element (IRE), and the enhanced IRP1 activity continued over 24 h. On the other hand, no induction of increased IRP1 binding to IRE was observed in rodent cells exposed to formaldehyde. Previously, we observed stimulation of EpRE-mediated ferritin mRNA expression in the cells exposed to hydrogen peroxide. However, paraquat did not induce any transcriptional activation of ferritin genes. These results suggest that intracellular iron may be involved in paraquat-mediated cytotoxicity and the influence of paraquat on iron metabolism differs from that of hydrogen peroxide.
Ayaki
Hitoshi
H
Division of Public Health, Department of Environmental Health and Safety, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. ayaki@med.kobe-u.ac.jp
Lee
Myeong Jin
MJ
Sumino
Kimiaki
K
Nishio
Hisahide
H
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015152:Blotting, Northern; D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection; D003676:Deferoxamine / Q000494:pharmacology; D005293:Ferritins / Q000096:biosynthesis / Q000235:genetics; D005557:Formaldehyde / Q000633:toxicity*; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D035925:Iron-Regulatory Proteins / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010269:Paraquat / Q000633:toxicity*; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D020218:Response Elements; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors
D000975:Antioxidants; D007502:Iron Chelating Agents; D035925:Iron-Regulatory Proteins; D011759:Pyrrolidines; D012333:RNA, Messenger; D013859:Thiocarbamates; D005557:Formaldehyde; C020972:pyrrolidine dithiocarbamic acid; D005293:Ferritins; D007501:Iron; D003676:Deferoxamine; D010269:Paraquat