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dc.contributor.authorZheng, Ming
dc.contributor.authorZhang, Haili
dc.contributor.authorDill, David L
dc.contributor.authorClark, J David
dc.contributor.authorTu, Susan
dc.contributor.authorYablonovitch, Arielle L
dc.contributor.authorTan, Meng How
dc.contributor.authorZhang, Rui
dc.contributor.authorRujescu, Dan
dc.contributor.authorWu, Manhong
dc.contributor.authorTessarollo, Lino
dc.contributor.authorVieira, Wilfred
dc.contributor.authorGottesman, Michael M
dc.contributor.authorDeng, Suhua
dc.contributor.authorEberlin, Livia S
dc.contributor.authorZare, Richard N
dc.contributor.authorBillard, Jean-Martin
dc.contributor.authorGillet, Jean-Pierre
dc.contributor.authorLi, Jin Billy
dc.contributor.authorPeltz, Gary
dc.date.accessioned2016-02-21T08:51:25Z
dc.date.available2016-02-21T08:51:25Z
dc.date.issued2015-02-03
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.
dc.identifier.issn1549-1676
dc.identifier.pmid25647612
dc.identifier.doi10.1371/journal.pmed.1001782
dc.identifier.urihttp://hdl.handle.net/10754/596826
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.
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.
dc.publisherPublic Library of Science (PLoS)
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 credited
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subject.meshPolymorphism, Single Nucleotide
dc.subject.meshAlleles
dc.titleThe role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.
dc.typeArticle
dc.identifier.journalPLOS Medicine
dc.identifier.pmcidPMC4315575
dc.contributor.institutionDepartment of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America.
dc.contributor.institutionComputer Science, Stanford University, Stanford, California, United States of America.
dc.contributor.institutionVeterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
dc.contributor.institutionDepartment of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
dc.contributor.institutionDepartment of Psychiatry, University Of Halle, Halle, Germany.
dc.contributor.institutionCenter for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
dc.contributor.institutionLaboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
dc.contributor.institutionDepartment of Pathology, Stanford University, Stanford, California, United States of America.
dc.contributor.institutionDepartment of Chemistry, Stanford University, Stanford, California, United States of America.
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.
kaust.grant.programAcademic Excellence Alliance (AEA)
refterms.dateFOA2018-06-13T14:20:41Z


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This 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 credited
Except where otherwise noted, this item's license is described as This 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 credited