Identification of potential biomarkers of P-glycoprotein substrate neurotoxicity in transgenic mice expressing the mutated canine ABCB1 gene
| Autor: | Marla D. Swain, Yolanda L. Jones, Heidi Swaim, Xiaolin Wu, Min Zhu, Haile F. Yancy, Michael J. Myers, Yi Ming, Christine M. Deaver |
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| Rok vydání: | 2014 |
| Předmět: |
Genetically modified mouse
Digoxin Insecticides ATP Binding Cassette Transporter Subfamily B Cardiotonic Agents Genotype Transgene Mutant Organic Anion Transporters Mice Transgenic Biology medicine.disease_cause Substrate Specificity Mice Dogs Gene expression medicine Animals P-glycoprotein Mutation General Veterinary Microarray analysis techniques Neurotoxicity General Medicine medicine.disease Molecular biology Gene Expression Regulation biology.protein Neurotoxicity Syndromes Biomarkers |
| Zdroj: | American Journal of Veterinary Research. 75:1104-1110 |
| ISSN: | 0002-9645 |
| Popis: | Objective—To identify biomarkers of P-glycoprotein (P-gp) substrate neurotoxicity in transgenic mice expressing the mutant canine ABCB1 gene (ABCB1-1Δ). Animals—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). Procedures—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 and Clinical Relevance—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. |
| Databáze: | OpenAIRE |
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