ArticlePLoS medicine2015
The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.
Article in PLoS medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 29 citations in OpenAlex.
- Trial
- A Murine Database of Structural Variants Identifies A Candidate Gene for a Spontaneous Murine Lymphoma Model.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Abcb5-deficient mice show a subtle, pleiotropic phenotype indicating a role for this transporter in intermediary metabolism.iScience · 2025Article
- A Murine Database of Structural Variants Enables the Genetic Architecture of a Spontaneous Murine Lymphoma to be Characterized.bioRxiv : the preprint server for biology · 2025Article
- Twenty-first century mouse genetics is again at an inflection point.Lab animal · 2025Review
- The uniqueness of ABCB5 as a full transporter ABCB5FL and a half-transporter-like ABCB5β.Cancer drug resistance (Alhambra, Calif.) · 2024Review
- Neuron Navigator 1 (Nav1) regulates the response to cocaine in mice.Communications biology · 2023Article
- Analysis of structural variation among inbred mouse strains.BMC genomics · 2023Article
- Optimizing a therapy for opiate use disorders: Characterizing ondansetron pharmacokinetics in blood and brain.Clinical and translational science · 2023Article
- An automated multi-modal graph-based pipeline for mouse genetic discovery.Bioinformatics (Oxford, England) · 2022Article
- What Have We Learned (or Expect to) From Analysis of Murine Genetic Models Related to Substance Use Disorders?Frontiers in psychiatry · 2021Review
- The Effect of Population Structure on Murine Genome-Wide Association Studies.Frontiers in genetics · 2021Article
- Genetic variation in ABCB5 associates with risk of hepatocellular carcinoma.Journal of cellular and molecular medicine · 2020Article
- Article
- A Pharmacogenetic Discovery: Cystamine Protects Against Haloperidol-Induced Toxicity and Ischemic Brain Injury.Genetics · 2016Article
- The multiple PDZ domain protein Mpdz/MUPP1 regulates opioid tolerance and opioid-induced hyperalgesia.BMC genomics · 2016Article
Corrections and comments
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Authors and funding
20 authors at 5 institutions in 2 countries.
Funding
Abstract
backgroundWe 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
findingsA 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.
conclusionsABCB5 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.
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