Increased FasL expression correlates with apoptotic changes in granulocytes cultured with oxidized clozapine

Journal Article · Tue Aug 01 00:00:00 EDT 2006 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2006.01.008· OSTI ID:20850386

Husain, Zaheed ^[1]; Almeciga, Ingrid ^[1]; Delgado, Julio C ^[1]; Clavijo, Olga P ^[1]; Castro, Januario E ^[1]; Belalcazar, Viviana ^[1]; Pinto, Clara; Zuniga, Joaquin ^[1]; Romero, Viviana ^[1]; Yunis, Edmond J ^[2]

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1. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA (United States)
2. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA (United States) and Department of Pathology, Harvard Medical School, Boston, MA (United States)

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 H{sub 2}O{sub 2} 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.

• OSTI ID: 20850386
• Journal Information: Toxicology and Applied Pharmacology, Vol. 214, Issue 3; Other Information: DOI: 10.1016/j.taap.2006.01.008; PII: S0041-008X(06)00031-7; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACETATES
APOPTOSIS
DMSO
FLUORESCENCE
GENES
HEAT-SHOCK PROTEINS
HYDROGEN PEROXIDE
IMMUNOGLOBULINS
ISOTHIOCYANATES
MACROPHAGES
NEUTROPHILS
POLYMERASE CHAIN REACTION
RETINOIC ACID
TETRAZOLIUM
TOXICITY