title: Identification of potential biomarkers of P-glycoprotein substrate neurotoxicity in transgenic mice expressing the mutated canine ABCB1 gene.
abstract: OBJECTIVE
  To identify biomarkers of P-glycoprotein (P-gp) substrate neurotoxicity in transgenic mice expressing the mutant canine ABCB1 gene (ABCB1-1Δ).
  
  
  METHODS
  8 ABCB1 knock-in and knock-out transgenic mice expressing the ABCB1-1Δ gene and 8 control mice expressing the wild-type canine ABCB1 gene (ABCB1-WT).
  
  
  METHODS
  Groups including 2 ABCB1-1Δ mutant mice and 2 ABCB1-WT mice were administered the P-gp substrates ivermectin (10 mg/kg, SC), doramectin (10 mg/kg, SC), moxidectin (10 mg/kg, PO), or digoxin (1.53 mg/kg, SC). A toxicogenomic approach based on DNA microarrays was used to examine whole-genome expression changes in mice administered P-gp substrates.
  
  
  RESULTS
  Compared with control ABCB1-WT mice, ABCB1-1Δ mutant mice developed neurotoxic signs including ataxia, lethargy, and tremors similar to those reported for dogs with the ABCB1-1Δ mutation. Microarray analysis revealed that gene expression was altered in ABCB1-1Δ mutant mice, compared with findings for ABCB1-WT mice, following administration of the same P-gp substrates. Gene pathway analysis revealed that genes with a ≥ 2-fold gene expression change were associated with behavior and nervous system development and function. Moreover, 34 genes were altered in the ABCB1-1Δ mutant mice in all 4 drug treatment groups. These genes were also associated with behavior, which was identified as the top-ranked gene network.
  
  
  CONCLUSIONS
  These study data have facilitated understanding of the molecular mechanisms of neurotoxicosis in ABCB1-1Δ mutant mice following exposure to various P-gp substrates. Some genes appear to be potential biomarkers of P-gp substrate neurotoxicity that might be used to predict the safety of those drugs in dogs with the ABCB1-1Δ mutation.
authors.affiliation: Office of Research, Center for Veterinary Medicine, US FDA, 8401 Muirkirk Rd, Laurel, MD 20708.
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Yi
authors.initials: Y
authors.lastname: Ming
authors.forename: Heidi
authors.initials: H
authors.lastname: Swaim
authors.forename: Marla D
authors.initials: MD
authors.lastname: Swain
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Myers
authors.forename: Christine
authors.initials: C
authors.lastname: Deaver
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wu
authors.forename: Yolanda L
authors.initials: YL
authors.lastname: Jones
authors.forename: Haile F
authors.initials: HF
authors.lastname: Yancy
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers; D002316:Cardiotonic Agents / Q000378:metabolism / Q000633:toxicity*; D004077:Digoxin / Q000378:metabolism / Q000633:toxicity*; D004285:Dogs; D005786:Gene Expression Regulation / Q000502:physiology; D005838:Genotype; D007306:Insecticides / Q000378:metabolism / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D020258:Neurotoxicity Syndromes / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D015415:Biomarkers; D002316:Cardiotonic Agents; D007306:Insecticides; D027361:Organic Anion Transporters; D004077:Digoxin