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

Handle URI:
http://hdl.handle.net/10754/596826
Title:
The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.
Authors:
Zheng, Ming; Zhang, Haili; Dill, David L; Clark, J David; Tu, Susan; Yablonovitch, Arielle L; Tan, Meng How; Zhang, Rui; Rujescu, Dan; Wu, Manhong; Tessarollo, Lino; Vieira, Wilfred; Gottesman, Michael M; Deng, Suhua; Eberlin, Livia S; Zare, Richard N; Billard, Jean-Martin; Gillet, Jean-Pierre; Li, Jin Billy; Peltz, Gary
Abstract:
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.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.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.
Citation:
Zheng M, Zhang H, Dill DL, Clark JD, Tu S, et al. (2015) The Role of Abcb5 Alleles in Susceptibility to Haloperidol-Induced Toxicity in Mice and Humans. PLOS Medicine 12: e1001782. Available: http://dx.doi.org/10.1371/journal.pmed.1001782.
Publisher:
Public Library of Science (PLoS)
Journal:
PLOS Medicine
Issue Date:
3-Feb-2015
DOI:
10.1371/journal.pmed.1001782
PubMed ID:
25647612
PubMed Central ID:
PMC4315575
Type:
Article
ISSN:
1549-1676
Sponsors:
GP and MZ were partially supported by funding from a transformative RO1 award (1R01DK090992-01) DLD was supported by a King Abdullah University of Science and Technology (KAUST) research grant under the KAUST Stanford Academic Excellence Alliance program. ST was supported by Stanford's CURIS program for summer research interns. LSE was supported by a postdoctoral fellowship from the Center for Molecular Analysis and Design (CMAD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Appears in Collections:
Publications Acknowledging KAUST Support

Full metadata record

DC FieldValue Language
dc.contributor.authorZheng, Mingen
dc.contributor.authorZhang, Hailien
dc.contributor.authorDill, David Len
dc.contributor.authorClark, J Daviden
dc.contributor.authorTu, Susanen
dc.contributor.authorYablonovitch, Arielle Len
dc.contributor.authorTan, Meng Howen
dc.contributor.authorZhang, Ruien
dc.contributor.authorRujescu, Danen
dc.contributor.authorWu, Manhongen
dc.contributor.authorTessarollo, Linoen
dc.contributor.authorVieira, Wilfreden
dc.contributor.authorGottesman, Michael Men
dc.contributor.authorDeng, Suhuaen
dc.contributor.authorEberlin, Livia Sen
dc.contributor.authorZare, Richard Nen
dc.contributor.authorBillard, Jean-Martinen
dc.contributor.authorGillet, Jean-Pierreen
dc.contributor.authorLi, Jin Billyen
dc.contributor.authorPeltz, Garyen
dc.date.accessioned2016-02-21T08:51:25Zen
dc.date.available2016-02-21T08:51:25Zen
dc.date.issued2015-02-03en
dc.identifier.citationZheng M, Zhang H, Dill DL, Clark JD, Tu S, et al. (2015) The Role of Abcb5 Alleles in Susceptibility to Haloperidol-Induced Toxicity in Mice and Humans. PLOS Medicine 12: e1001782. Available: http://dx.doi.org/10.1371/journal.pmed.1001782.en
dc.identifier.issn1549-1676en
dc.identifier.pmid25647612en
dc.identifier.doi10.1371/journal.pmed.1001782en
dc.identifier.urihttp://hdl.handle.net/10754/596826en
dc.description.abstractWe 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.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.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.en
dc.description.sponsorshipGP and MZ were partially supported by funding from a transformative RO1 award (1R01DK090992-01) DLD was supported by a King Abdullah University of Science and Technology (KAUST) research grant under the KAUST Stanford Academic Excellence Alliance program. ST was supported by Stanford's CURIS program for summer research interns. LSE was supported by a postdoctoral fellowship from the Center for Molecular Analysis and Design (CMAD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.publisherPublic Library of Science (PLoS)en
dc.rightsThis is an open access article distributed under the terms of the , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are crediteden
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subject.meshPolymorphism, Single Nucleotideen
dc.subject.meshAllelesen
dc.titleThe role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.en
dc.typeArticleen
dc.identifier.journalPLOS Medicineen
dc.identifier.pmcidPMC4315575en
dc.contributor.institutionDepartment of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America.en
dc.contributor.institutionComputer Science, Stanford University, Stanford, California, United States of America.en
dc.contributor.institutionVeterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.en
dc.contributor.institutionDepartment of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.en
dc.contributor.institutionDepartment of Psychiatry, University Of Halle, Halle, Germany.en
dc.contributor.institutionCenter for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.en
dc.contributor.institutionLaboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.en
dc.contributor.institutionDepartment of Pathology, Stanford University, Stanford, California, United States of America.en
dc.contributor.institutionDepartment of Chemistry, Stanford University, Stanford, California, United States of America.en
dc.contributor.institutionLaboratory of Molecular Cancer Biology, Molecular Physiology Research Unit (URPhyM), Namur Research Institute for Life Sciences (NARILIS), Faculty of Medicine, University of Namur, Belgium.en
kaust.grant.programAcademic Excellence Alliance (AEA)en

Related articles on PubMed

All Items in KAUST are protected by copyright, with all rights reserved, unless otherwise indicated.