Potential clozapine target sites on peripheral hematopoietic cells and stromal cells of the bone marrow.
The antipsychotic drug clozapine, acts via interaction with selective neurotransmitter receptor systems. Its use however, is associated with life-threatening agranulocytosis. The mechanism by which this occurs and its possible relationship with the drug's atypicality remain unclear. As a first step in identifying mechanistic pathways involved, profiling of neurotransmitter receptors on human neutrophils, mononuclear and bone marrow stromal cells as putative targets for clozapine-mediated toxicity was undertaken. Expression of mRNA encoding dopaminergic d2, d3, d4; serotonergic 5ht2a, 5ht2c, 5ht3, 5ht6, 5ht7; adrenergic alpha1a, alpha2; histaminergic h1 and muscarinic m1, m2, m3, m4, m5 receptors was analyzed by reverse transcription-polymerase chain reaction methods. While 5ht2c, 5ht6, m1 and m2 mRNA were undetected, the presence of the other receptors indicates sites at which clozapine could bind and induce toxicity of neutrophils and stromal components which regulate granulopoiesis. The functional significance of differential receptor expression while unknown, may argue for neural regulation of hematopoiesis.
Pereira
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A
Division of Molecular Schizophrenia, Mental Health Research Institute of Victoria, Parkville, Victoria, Australia. APereira@hri.edu.au
McLaren
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A
Bell
W R
WR
Copolov
D
D
Dean
B
B
D001483:Base Sequence; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000378:metabolism*; D002478:Cells, Cultured; D003024:Clozapine / Q000378:metabolism*; D018076:DNA, Complementary / Q000032:analysis; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D017981:Receptors, Neurotransmitter / Q000096:biosynthesis*
D018076:DNA, Complementary; D012333:RNA, Messenger; D017981:Receptors, Neurotransmitter; D003024:Clozapine