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 LC50 of 0.3 and 2 muM, 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 Ca2+ in PC12 cells, which were almost completely blocked by flufenamic acid (FFA), an inhibitor of non-selective cation channel. BAPTA-AM, an intracellular Ca2+ chelator inhibited the thiram- and ziraminduced apoptotic cell death. These results suggest that thiram and ziram induce apoptotic neuronal cell death by Ca2+ influx through non-selective cation channels. The present study may provide a clue for understanding the mechanism of neurotoxicity of thiram and ziram. (C) 2003 Published by Elsevier Science Inc.