Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells
Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells
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DOI：
10.1016/j.taap.2016.06.028
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发表时间：
2016-09-01
影响因子：
3.8
通讯作者：
Noda, Yukihiro
中科院分区：
文献类型：
--
作者：
Goto, Aya;Mouri, Akihiro;Noda, Yukihiro
氯氮平是治疗难治性精神分裂症的有效抗精神病药，但可引起致命的造血毒性，如粒细胞缺乏症。为探讨氯氮平的造血毒性机制，我们建立了一种体外检测系统，以HL-60细胞为研究对象，研究了氯氮平对造血功能的影响。用全反式维甲酸（ATRA）诱导HL-60细胞分化为三种状态：未分化的HL-60细胞、ATRA诱导的粒细胞分化细胞和ATRA诱导的粒细胞分化细胞。通过分析细胞存活、细胞增殖、粒细胞分化、凋亡和坏死来评价造血毒性。在未分化的HL-60细胞和ATRA分化的粒细胞中，氯氮平（50和100 μ M）和多柔比星（0.2 μ M）均降低细胞存活率，但奥氮平（1-100 μ M）没有。在粒细胞分化5天，氯氮平，即使在25 μ M的浓度，降低生存不影响粒细胞分化，增加半胱天冬酶活性，并引起细胞凋亡，而不是坏死。HL-60细胞表达组胺H-4受体mRNA，而在粒细胞分化过程中表达逐渐下降。硫代哌丁胺，组胺H-4受体拮抗剂，和DEVD-FMK，半胱天冬酶-3抑制剂，对氯氮平诱导的存活率降低，但不是活细胞计数的保护。4-甲基组胺，组胺H-4受体激动剂，降低存活率和活细胞计数，如氯氮平。粒细胞分化的HL-60细胞在体外试验条件下易受氯氮平诱导的造血毒性的影响。组胺H-4受体通过凋亡参与氯氮平诱导的造血毒性的发展，并可能是通过粒细胞分化防止其发生的潜在靶点。(C)2016 Elsevier Inc. All rights reserved.
Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100 mu M) and doxorubicin (0.2 mu M) decreased the cell survival rate, but olanzapine (1-100 mu M) did not. Under granulocytic differentiation for 5 days, clozapine, even at a concentration of 25 mu M, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H-4 receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H-4 receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H-4 receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H-4 receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic differentiation. (C) 2016 Elsevier Inc. All rights reserved.