TY - JOUR
T1 - Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity
T2 - Vulnerability under granulocytic differentiation of HL-60 cells
AU - Goto, Aya
AU - Mouri, Akihiro
AU - Nagai, Tomoko
AU - Yoshimi, Akira
AU - Ukigai, Mako
AU - Tsubai, Tomomi
AU - Hida, Hirotake
AU - Ozaki, Norio
AU - Noda, Yukihiro
N1 - Funding Information:
This study was supported in part by The ‘Academic Frontier’ Project for Private Universities (2007–2011); Grants-in-Aid for Scientific Research C ( 24590219 , 16K08421 ) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan , The Adaptable and Seamless Technology Transfer Program Through Target-driven R&D, Japan Science and Technology Agency ( AS251Z03018 ), Research on Risk of Chemical Substances (2008–2010), Health and Labor Science Research Grants supported by the Ministry of Health, Labor and Welfare (MHLW) , Meijo University Research Institute Grant , and Smoking Research Foundation Grant for Biomedical Research (SRF) . We would like to thank Mr. Minoru Tanaka of Division for Medical Research Engineering, Graduate School of Medicine, Nagoya University for technical advice in this study, Dr. Tomohiro Mizuno of Faculty of Pharmacy, Meijo University, for helpful advice in this study, Ms. Hiromi Ohguchi of Faculty of Pharmacy, Meijo University, for technical assistance in this study.
Publisher Copyright:
© 2016
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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 μM) and doxorubicin (0.2 µM) decreased the cell survival rate, but olanzapine (1–100 µM) did not. Under granulocytic differentiation for 5 days, clozapine, even at a concentration of 25 μM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H4 receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H4 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 H4 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 H4 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.
AB - 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 μM) and doxorubicin (0.2 µM) decreased the cell survival rate, but olanzapine (1–100 µM) did not. Under granulocytic differentiation for 5 days, clozapine, even at a concentration of 25 μM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H4 receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H4 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 H4 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 H4 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.
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U2 - 10.1016/j.taap.2016.06.028
DO - 10.1016/j.taap.2016.06.028
M3 - Article
C2 - 27368152
AN - SCOPUS:84978101132
SN - 0041-008X
VL - 306
SP - 8
EP - 16
JO - Toxicology and applied pharmacology
JF - Toxicology and applied pharmacology
ER -