PMID- 36674761
OWN - NLM
STAT- MEDLINE
DCOM- 20230124
LR  - 20230201
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 24
IP  - 2
DP  - 2023 Jan 8
TI  - The Role of Myeloperoxidase in Clozapine-Induced Inflammation: A Mechanistic 
      Update for Idiosyncratic Drug-Induced Agranulocytosis.
LID - 10.3390/ijms24021243 [doi]
LID - 1243
AB  - The risk of idiosyncratic drug-induced agranulocytosis (IDIAG) markedly 
      constrains the use of clozapine, a neuroleptic with unparalleled efficacy. Most 
      clozapine patients experience an early inflammatory response, likely a necessary 
      step in IDIAG onset. However, most patients do not progress to IDIAG, presumably 
      because of the requirement of specific human leukocyte antigen (HLA) haplotypes, 
      T cell receptors, and other unknown factors. We established that clozapine 
      activates inflammasomes and that myeloperoxidase bioactivation of clozapine 
      generates neoantigens, but the connection between these early mechanistic events 
      remained unknown and, thus, was the aim of this work. We found that the 
      myeloperoxidase inhibitor PF-1355 attenuated myeloperoxidase activity in phorbol 
      myristate acetate (PMA)-differentiated THP-1 macrophages, and it also attenuated 
      clozapine-induced release of inflammatory mediators (e.g., IL-1beta, CXCL1, and 
      C-reactive protein). In vivo, pretreatment of Sprague Dawley rats with PF-1355 
      significantly attenuated clozapine-induced increases in neutrophil mobilization 
      from the bone marrow to the blood and spleen, as determined using differential 
      blood counts and flow cytometry. Moreover, the clozapine-triggered release of 
      inflammatory mediators (e.g., IL-1beta, calprotectin, CXCL1, and alpha-1-acid 
      glycoprotein) from the liver, spleen, and bone marrow was dampened by 
      myeloperoxidase inhibition. These data support the working hypothesis that 
      oxidation of clozapine to a reactive metabolite by myeloperoxidase is critical 
      for induction of the inflammatory response to clozapine. Ultimately, a better 
      mechanistic understanding of the early events involved in the immune response to 
      clozapine may elucidate ways to prevent IDIAG, enabling safer, more frequent 
      therapeutic use of this and potentially other highly efficacious drugs.
FAU - Sernoskie, Samantha Christine
AU  - Sernoskie SC
AUID- ORCID: 0000-0002-0904-8516
AD  - Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of 
      Toronto, Toronto, ON M5S 3M2, Canada.
FAU - Jee, Alison
AU  - Jee A
AUID- ORCID: 0000-0002-8136-0002
AD  - Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, 
      University of Toronto, Toronto, ON M5S 1A8, Canada.
FAU - Uetrecht, Jack
AU  - Uetrecht J
AD  - Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of 
      Toronto, Toronto, ON M5S 3M2, Canada.
AD  - Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, 
      University of Toronto, Toronto, ON M5S 1A8, Canada.
LA  - eng
GR  - 512780/CAPMC/CIHR/Canada
PT  - Journal Article
DEP - 20230108
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - J60AR2IKIC (Clozapine)
RN  - 0 
      (2-(6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide)
RN  - EC 1.11.1.7 (Peroxidase)
RN  - 0 (Antipsychotic Agents)
RN  - 0 (Coloring Agents)
RN  - 0 (Inflammation Mediators)
SB  - IM
MH  - Humans
MH  - Rats
MH  - Animals
MH  - *Clozapine/adverse effects
MH  - Peroxidase/metabolism
MH  - Rats, Sprague-Dawley
MH  - *Antipsychotic Agents/adverse effects
MH  - *Neutropenia
MH  - Inflammation/drug therapy
MH  - Coloring Agents
MH  - Inflammation Mediators
PMC - PMC9862306
OTO - NOTNLM
OT  - MPO
OT  - Sprague Dawley rats
OT  - THP-1 macrophages
OT  - clozapine
OT  - idiosyncratic drug-induced agranulocytosis
OT  - inflammation
OT  - myeloperoxidase
COIS- The authors declare no conflict of interest.
EDAT- 2023/01/22 06:00
MHDA- 2023/01/25 06:00
PMCR- 2023/01/08
CRDT- 2023/01/21 01:26
PHST- 2022/12/08 00:00 [received]
PHST- 2023/01/03 00:00 [revised]
PHST- 2023/01/06 00:00 [accepted]
PHST- 2023/01/21 01:26 [entrez]
PHST- 2023/01/22 06:00 [pubmed]
PHST- 2023/01/25 06:00 [medline]
PHST- 2023/01/08 00:00 [pmc-release]
AID - ijms24021243 [pii]
AID - ijms-24-01243 [pii]
AID - 10.3390/ijms24021243 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 Jan 8;24(2):1243. doi: 10.3390/ijms24021243.