Thiram and ziram stimulate non-selective cation channel and induce apoptosis in PC12 cells.
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.
Sook Han
Myoung
M
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.
Shin
Kum Joo
KJ
Kim
Yun Hee
YH
Kim
Sun Hee
SH
Lee
Taehoon
T
Kim
Euikyung
E
Ho Ryu
Sung
S
Suh
Pann Ghill
PG
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*
D007473:Ion Channels; C491711:nonselective cation channel protein, rat; D013893:Thiram; D015039:Ziram; D002118:Calcium