Increased FasL expression correlates with apoptotic changes in granulocytes cultured with oxidized clozapine
Increased FasL expression correlates with apoptotic changes in granulocytes cultured with oxidized clozapine
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DOI：
10.1016/j.taap.2006.01.008
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发表时间：
2006-08-01
影响因子：
3.8
通讯作者：
Yunis, Edmond J.
中科院分区：
文献类型：
--
作者：
Husain, Zaheed;Almeciga, Ingrid;Yunis, Edmond J.
氯氮平与1%的粒细胞缺乏症的发生率有关。氯氮平的氧化中间代谢物的形成与直接多形核(PMN)毒性有关。我们利用两个不同的系统来分析氧化氯氮平在诱导处理细胞凋亡中的作用。0.1mM H_2O_2与氯氮平(0~10mM)共同孵育的人PMN细胞表面CD16表达逐渐减少，细胞凋亡率增加。RT-PCR分析显示，氯氮平处理的PMN细胞CD16表达降低，而FasL基因表达增加。在处理的细胞中没有观察到结构性Fas表达的变化。在维甲酸(RA)诱导分化的HL-60细胞中，经氯氮平处理后，FasL的表达也有类似的增加，但CD16基因的表达没有相关的变化。我们的结果表明，在氧化氯氮平诱导的中性粒细胞凋亡中，FasL基因的表达增加，这表明氯氮平处理的粒细胞中的凋亡涉及Fas/FasL相互作用，该相互作用启动了导致氯氮平诱导的粒细胞缺乏症的一系列事件。(C)2006 Elsevier Inc.保留所有权利。
Clozapine has been associated with a 1% incidence of agranulocytosis. The formation of an oxidized intermediate clozapine metabolite has been implicated in direct polymorphonuclear (PMN) toxicity. We utilized two separate systems to analyze the role of oxidized clozapine in inducing apoptosis in treated cells. Human PMN cells incubated with clozapine (0-10 mu M) in the presence of 0.1 mM H2O2 demonstrated a progressive decrease of surface CD16 expression along with increased apoptosis. RT-PCR analysis showed decreased CD16 but increased FasL gene expression in clozapine-treated PMN cells. No change in constitutive Fas expression was observed in treated cells. In HL-60 cells induced to differentiate with retinoic acid (RA), a similar increase in FasL expression, but no associated changes in CD16 gene expression, was observed following clozapine treatments. Our results demonstrate increased FasL gene expression in oxidized clozapine-induced apoptotic neutrophils suggesting that apoptosis in granulocytes treated with clozapine involves Fas/FasL interaction that initiates a cascade of events leading to clozapine-induced agranulocytosis. (c) 2006 Elsevier Inc. All rights reserved..