Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity

Vulnerability under granulocytic differentiation of HL-60 cells

Aya Goto, Akihiro Mouri, Tomoko Nagai, Akira Yoshimi, Mako Ukigai, Tomomi Tsubai, Hirotake Hida, Norio Ozaki, Yukihiro Noda

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)8-16
Number of pages9
JournalToxicology and Applied Pharmacology
Volume306
DOIs
Publication statusPublished - 01-09-2016

Fingerprint

Histamine Receptors
Clozapine
HL-60 Cells
Histamine
Toxicity
Tretinoin
thioperamide
olanzapine
Apoptosis
Assays
Cell Survival
Necrosis
Cell Count
Cells
Agranulocytosis
Caspase Inhibitors
Hematopoiesis
Cell proliferation
Caspases
Caspase 3

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology

Cite this

Goto, Aya ; Mouri, Akihiro ; Nagai, Tomoko ; Yoshimi, Akira ; Ukigai, Mako ; Tsubai, Tomomi ; Hida, Hirotake ; Ozaki, Norio ; Noda, Yukihiro. / Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity : Vulnerability under granulocytic differentiation of HL-60 cells. In: Toxicology and Applied Pharmacology. 2016 ; Vol. 306. pp. 8-16.
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Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity : Vulnerability under granulocytic differentiation of HL-60 cells. / Goto, Aya; Mouri, Akihiro; Nagai, Tomoko; Yoshimi, Akira; Ukigai, Mako; Tsubai, Tomomi; Hida, Hirotake; Ozaki, Norio; Noda, Yukihiro.

In: Toxicology and Applied Pharmacology, Vol. 306, 01.09.2016, p. 8-16.

Research output: Contribution to journalArticle

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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

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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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