有機(jī)磷藥物敵百蟲(chóng)（trichlorfon）用途非常廣泛,，在農(nóng)業(yè)上一直被作為殺蟲(chóng)劑用于植物保護(hù)，在動(dòng)物醫(yī)學(xué)上則被用作驅(qū)蟲(chóng)劑治療內(nèi)外寄生蟲(chóng)病,，而在醫(yī)學(xué)臨床上則被用作抗血吸蟲(chóng)病的治療,，在20世紀(jì)還一直被用于神經(jīng)退行性疾病阿爾茨海默病的治療。然而,，最近的研究發(fā)現(xiàn),，敵百蟲(chóng)作為膽堿能抑制劑除了具有急性毒性外，還可引發(fā)遲發(fā)性神經(jīng)毒性（OPIDN）及導(dǎo)致其他慢性毒性癥狀,。動(dòng)物試驗(yàn)顯示,，敵百蟲(chóng)可引起腦皮層神經(jīng)細(xì)胞凋亡，但發(fā)生機(jī)制并不清楚,。
近日,，中國(guó)科學(xué)院動(dòng)物研究所伍一軍研究組利用培養(yǎng)神經(jīng)細(xì)胞模型研究了敵百蟲(chóng)致神經(jīng)細(xì)胞凋亡的機(jī)理，流式細(xì)胞術(shù)分析顯示,，敵百蟲(chóng)及其降解代謝物敵敵畏均可引起神經(jīng)細(xì)胞凋亡,，并呈濃度依賴關(guān)系，蛋白質(zhì)印跡分析則顯示，敵百蟲(chóng)引起細(xì)胞caspase-12降低而活化態(tài)的caspase-12增加,，提示敵百蟲(chóng)引起的細(xì)胞凋亡可通過(guò)內(nèi)質(zhì)網(wǎng)途徑觸發(fā),，敵百蟲(chóng)處理后細(xì)胞內(nèi)鈣離子濃度增加，而在用鈣通道阻斷劑及鈣相關(guān)受體抑制劑處理后不僅這種敵百蟲(chóng)誘導(dǎo)的細(xì)胞內(nèi)鈣增加減少,，而且細(xì)胞凋亡率以及與內(nèi)質(zhì)網(wǎng)途徑有關(guān)的凋亡蛋白caspase-12和活化態(tài)的caspase-3水平也大幅度降低,。此外，敵百蟲(chóng)誘導(dǎo)的神經(jīng)細(xì)胞凋亡可被PMA所抑制,。上述結(jié)果表明,，與鈣相關(guān)的內(nèi)質(zhì)網(wǎng)應(yīng)激是導(dǎo)致敵百蟲(chóng)細(xì)胞毒性的機(jī)制。（生物谷Bioon.com）
生物谷推薦原始出處：
Chemico-Biological Interactions 14 September 2009 doi:10.1016/j.cbi.2009.03.004
Trichlorfon induces apoptosis in SH-SY5Y neuroblastoma cells via the endoplasmic reticulum?
Cheng-Yun Liua, b, Ping-An Changa and Yi-Jun Wua, ,
aLaboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Datunlu Road, Beijing 100101, PR China
bGraduate School of the Chinese Academy of Sciences, Beijing 100039, PR China
This study investigated the role of the endoplasmic reticulum pathway in apoptosis induced by trichlorfon in SH-SY5Y human neuroblastoma cells. Flow cytometric analysis demonstrated that trichlorfon and its degradation product dichlorvos-induced apoptosis in a dose-dependent manner and Hoechst 33342 staining experiments revealed trichlorfon/dichlorvos-induced nucleus condensation. Western blot analysis indicated decreased expression of caspase-12 and increased activated caspase-12 in trichlorfon-treated cells compared to a control, suggesting that trichlorfon may induce apoptosis in SH-SY5Y partly via the endoplasmic reticulum. Intracellular Ca2+ level ([Ca2+]i) in SH-SY5Y cells increased after treatment with trichlorfon but was significantly reduced by pre-treatment with a combination of a calcium channel blocker, an inositol trisphosphate receptor inhibitor, and a ryanodine receptor inhibitor. Percent apoptosis and activated caspase-3 and caspase-12 decreased in pre-treated cells compared to those treated with trichlorfon alone. Trichlorfon-induced apoptosis was also inhibited by the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA). These results suggest that endoplasmic reticulum stress, which is related to calcium, may be involved in the cytotoxicity of trichlorfon.
