TY - JOUR
T1 - The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.
AU - Zheng, Ming
AU - Zhang, Haili
AU - Dill, David L
AU - Clark, J David
AU - Tu, Susan
AU - Yablonovitch, Arielle L
AU - Tan, Meng How
AU - Zhang, Rui
AU - Rujescu, Dan
AU - Wu, Manhong
AU - Tessarollo, Lino
AU - Vieira, Wilfred
AU - Gottesman, Michael M
AU - Deng, Suhua
AU - Eberlin, Livia S
AU - Zare, Richard N
AU - Billard, Jean-Martin
AU - Gillet, Jean-Pierre
AU - Li, Jin Billy
AU - Peltz, Gary
N1 - KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: 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.
This publication acknowledges KAUST support, but has no KAUST affiliated authors.
PY - 2015/2/3
Y1 - 2015/2/3
N2 - 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.
AB - 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.
UR - http://hdl.handle.net/10754/596826
UR - https://dx.plos.org/10.1371/journal.pmed.1001782
UR - http://www.scopus.com/inward/record.url?scp=84924352527&partnerID=8YFLogxK
U2 - 10.1371/journal.pmed.1001782
DO - 10.1371/journal.pmed.1001782
M3 - Article
C2 - 25647612
SN - 1549-1676
VL - 12
SP - e1001782
JO - PLoS Medicine
JF - PLoS Medicine
IS - 2
ER -