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PLoS Med. 2015 Feb 3;12(2):e1001782. doi: 10.1371/journal.pmed.1001782. eCollection 2015 Feb.

The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.

Author information

1
Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America.
2
Computer Science, Stanford University, Stanford, California, United States of America.
3
Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
4
Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
5
Department of Psychiatry, University Of Halle, Halle, Germany.
6
Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
7
Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
8
Department of Pathology, Stanford University, Stanford, California, United States of America.
9
Department of Chemistry, Stanford University, Stanford, California, United States of America.
10
Laboratory of Molecular Cancer Biology, Molecular Physiology Research Unit (URPhyM), Namur Research Institute for Life Sciences (NARILIS), Faculty of Medicine, University of Namur, Belgium.

Abstract

BACKGROUND:

We know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study.

METHODS AND FINDINGS:

A whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered.

CONCLUSIONS:

ABCB5 alleles alter susceptibility to HIT in mouse and humans. This discovery leads to a new model that (at least in part) explains inter-individual differences in susceptibility to a drug-induced CNS toxicity.

PMID:
25647612
PMCID:
PMC4315575
DOI:
10.1371/journal.pmed.1001782
[Indexed for MEDLINE]
Free PMC Article

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