title: Thiram and ziram stimulate non-selective cation channel and induce apoptosis in PC12 cells.
abstract: The neurotoxicity of dithiocarbamates has been previously reported, however, the detailed mechanism underlying the neurotoxicity is still not fully understood. Among the dithiocarbamates, we investigated thiram and ziram in a neuronal-like pheochromocytoma (PC12) cells. Thiram and ziram strongly induced cell death in both dose- and time-dependent manners with the LC(50) of 0.3 and 2 microM, respectively. The cell death showed typical apoptotic features, such as DNA fragmentation and an increase of subdiploidy nuclei. Interestingly, both thiram and ziram induced rapid and sustained increases of intracellular Ca(2+) in PC12 cells, which were almost completely blocked by flufenamic acid (FFA), an inhibitor of non-selective cation channel. BAPTA-AM, an intracellular Ca(2+) chelator, inhibited the thiram- and ziram-induced apoptotic cell death. These results suggest that thiram and ziram induce apoptotic neuronal cell death by Ca(2+) influx through non-selective cation channels. The present study may provide a clue for understanding the mechanism of neurotoxicity of thiram and ziram.
authors.affiliation: Division of Molecular and Life Sciences, Department of Life Science, SIGMOL Institute of Molecular Medicine, SIGMOL Inc., Pohang University of Science and Technology, 790-784, Pohang, South Korea.
authors.forename: Myoung
authors.initials: M
authors.lastname: Sook Han
authors.forename: Kum Joo
authors.initials: KJ
authors.lastname: Shin
authors.forename: Yun Hee
authors.initials: YH
authors.lastname: Kim
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Taehoon
authors.initials: T
authors.lastname: Lee
authors.forename: Euikyung
authors.initials: E
authors.lastname: Kim
authors.forename: Sung
authors.initials: S
authors.lastname: Ho Ryu
authors.forename: Pann Ghill
authors.initials: PG
authors.lastname: Suh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007473:Ion Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D013893:Thiram / Q000494:pharmacology*; D015039:Ziram / Q000494:pharmacology*
chemical_list: D007473:Ion Channels; C491711:nonselective cation channel protein, rat; D013893:Thiram; D015039:Ziram; D002118:Calcium