title: The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.
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.
  
  
  RESULTS
  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.
authors: Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Ming
authors: M
authors: Zheng
authors: Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Haili
authors: H
authors: Zhang
authors: Computer Science, Stanford University, Stanford, California, United States of America.
authors: David L
authors: DL
authors: Dill
authors: Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
authors: J David
authors: JD
authors: Clark
authors: Computer Science, Stanford University, Stanford, California, United States of America.
authors: Susan
authors: S
authors: Tu
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Arielle L
authors: AL
authors: Yablonovitch
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Meng How
authors: MH
authors: Tan
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Rui
authors: R
authors: Zhang
authors: Department of Psychiatry, University Of Halle, Halle, Germany.
authors: Dan
authors: D
authors: Rujescu
authors: Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Manhong
authors: M
authors: Wu
authors: Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors: Lino
authors: L
authors: Tessarollo
authors: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Wilfred
authors: W
authors: Vieira
authors: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Michael M
authors: MM
authors: Gottesman
authors: Department of Pathology, Stanford University, Stanford, California, United States of America.
authors: Suhua
authors: S
authors: Deng
authors: Department of Chemistry, Stanford University, Stanford, California, United States of America.
authors: Livia S
authors: LS
authors: Eberlin
authors: Department of Chemistry, Stanford University, Stanford, California, United States of America.
authors: Richard N
authors: RN
authors: Zare
authors: Laboratory of Molecular Cancer Biology, Molecular Physiology Research Unit (URPhyM), Namur Research Institute for Life Sciences (NARILIS), Faculty of Medicine, University of Namur, Belgium.
authors: Jean-Martin
authors: JM
authors: Billard
authors: Laboratory of Molecular Cancer Biology, Molecular Physiology Research Unit (URPhyM), Namur Research Institute for Life Sciences (NARILIS), Faculty of Medicine, University of Namur, Belgium.
authors: Jean-Pierre
authors: JP
authors: Gillet
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Jin Billy
authors: JB
authors: Li
authors: Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Gary
authors: G
authors: Peltz
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006220:Haloperidol / Q000633:toxicity*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D020258:Neurotoxicity Syndromes / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C480744:ABCB5 protein, human; C573563:ABCB5 protein, mouse; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D014150:Antipsychotic Agents; D006220:Haloperidol
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