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.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.
Highlights
Little is known about the mechanisms regulating the entry of many drugs into the brain, or about the genetic mechanisms affecting susceptibility to many drug-induced central nervous system (CNS) toxicities
Several other factors indicated that Abcb5 was a likely candidate gene: (i) When the robustness of the mapping results were assessed by randomly deleting sets of strains and iteratively repeating the analysis, Abcb5 was among the top genes identified after the latency data were analyzed for treatment days 30, 60, or 120 (S4 Table). (ii) Among the 440 SNPs within or near Abcb5, eight missense SNPs divided the 17 strains into three haplotypic groupings with different latencies: group 1; group 2 (144–171 seconds; NZW, NZO); and group 3 (234 seconds, A/J)
Another codon changing SNP converted a serine, which is conserved in all vertebrates, to an alanine in the strain (A/J) with the highest latency. (iii) We investigated whether Abcb5 alleles could predict the measured latency for two inbred strains with extreme latency values (NON/ShiLtJ, 2.8 seconds; and NZL/LtJ, 211 seconds) whose genomic sequence was not yet characterized
Summary
Little is known about the mechanisms regulating the entry of many drugs into the brain, or about the genetic mechanisms affecting susceptibility to many drug-induced central nervous system (CNS) toxicities. Because of this lack of information, candidate drugs affecting the CNS have the lowest rate of survival during clinical development (
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