Loperamide‐induced expression of immune and inflammatory genes in Collies associated with ivermectin sensitivity
This study evaluated the impact of the ABCB1‐1Δ mutation in Collies which exhibited toxicity toward ivermectin, on changes in gene expression when given the unrelated ABCB1 substrate loperamide, to identify potential biomarkers predictive of drug safety. Thirty‐two healthy intact Collies consisting...
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| Published in: | Journal of veterinary pharmacology and therapeutics Vol. 39; no. 2; pp. 131 - 137 |
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| Main Authors: | , , , , |
| Format: | Journal Article |
| Language: | English |
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Blackwell Scientific Publications
01-04-2016
Blackwell Publishing Ltd |
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| Abstract | This study evaluated the impact of the ABCB1‐1Δ mutation in Collies which exhibited toxicity toward ivermectin, on changes in gene expression when given the unrelated ABCB1 substrate loperamide, to identify potential biomarkers predictive of drug safety. Thirty‐two healthy intact Collies consisting of dogs with either a wild‐type, heterozygous mutant, or homozygous mutant genotype were used. Whole blood samples were collected from Collies at 0 or 5 h following administration of loperamide at a dose of 0.10 mg/kg. Whole‐genome gene expression microarray was conducted to examine for changes in gene expression. Microarray analysis identified loperamide‐induced changes in gene expression which were specifically associated with ivermectin‐sensitive phenotypes in Collies possessing the ABCB1‐1Δ mutation. Gene pathway analysis further demonstrated that the altered genes are involved in immunological disease, cell death and survival, and cellular development. Thirteen genes, including CCL8 and IL‐8, were identified. Collie dogs harboring ABCB1‐1Δ mutation which also exhibited toxicity toward ivermectin demonstrated systematic responses following loperamide treatment exhibited by altered expression of genes involved in immune and inflammatory signaling pathways. Genes such as CCL8 and IL‐8 are potential biomarkers in whole blood that may predict the safety of loperamide in dogs with ABCB1‐1∆ mutation associated with ivermectin sensitivity. |
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| AbstractList | This study evaluated the impact of the ABCB1‐1Δ mutation in Collies which exhibited toxicity toward ivermectin, on changes in gene expression when given the unrelated ABCB1 substrate loperamide, to identify potential biomarkers predictive of drug safety. Thirty‐two healthy intact Collies consisting of dogs with either a wild‐type, heterozygous mutant, or homozygous mutant genotype were used. Whole blood samples were collected from Collies at 0 or 5 h following administration of loperamide at a dose of 0.10 mg/kg. Whole‐genome gene expression microarray was conducted to examine for changes in gene expression. Microarray analysis identified loperamide‐induced changes in gene expression which were specifically associated with ivermectin‐sensitive phenotypes in Collies possessing the ABCB1‐1Δ mutation. Gene pathway analysis further demonstrated that the altered genes are involved in immunological disease, cell death and survival, and cellular development. Thirteen genes, including CCL8 and IL‐8, were identified. Collie dogs harboring ABCB1‐1Δ mutation which also exhibited toxicity toward ivermectin demonstrated systematic responses following loperamide treatment exhibited by altered expression of genes involved in immune and inflammatory signaling pathways. Genes such as CCL8 and IL‐8 are potential biomarkers in whole blood that may predict the safety of loperamide in dogs with ABCB1‐1∆ mutation associated with ivermectin sensitivity. This study evaluated the impact of the ABCB 1‐1Δ mutation in Collies which exhibited toxicity toward ivermectin, on changes in gene expression when given the unrelated ABCB 1 substrate loperamide, to identify potential biomarkers predictive of drug safety. Thirty‐two healthy intact Collies consisting of dogs with either a wild‐type, heterozygous mutant, or homozygous mutant genotype were used. Whole blood samples were collected from Collies at 0 or 5 h following administration of loperamide at a dose of 0.10 mg/kg. Whole‐genome gene expression microarray was conducted to examine for changes in gene expression. Microarray analysis identified loperamide‐induced changes in gene expression which were specifically associated with ivermectin‐sensitive phenotypes in Collies possessing the ABCB 1‐1Δ mutation. Gene pathway analysis further demonstrated that the altered genes are involved in immunological disease, cell death and survival, and cellular development. Thirteen genes, including CCL 8 and IL ‐8, were identified. Collie dogs harboring ABCB 1‐1Δ mutation which also exhibited toxicity toward ivermectin demonstrated systematic responses following loperamide treatment exhibited by altered expression of genes involved in immune and inflammatory signaling pathways. Genes such as CCL 8 and IL ‐8 are potential biomarkers in whole blood that may predict the safety of loperamide in dogs with ABCB 1‐1∆ mutation associated with ivermectin sensitivity. This study evaluated the impact of the ABCB1-1 Delta mutation in Collies which exhibited toxicity toward ivermectin, on changes in gene expression when given the unrelated ABCB1 substrate loperamide, to identify potential biomarkers predictive of drug safety. Thirty-two healthy intact Collies consisting of dogs with either a wild-type, heterozygous mutant, or homozygous mutant genotype were used. Whole blood samples were collected from Collies at 0 or 5 h following administration of loperamide at a dose of 0.10 mg/kg. Whole-genome gene expression microarray was conducted to examine for changes in gene expression. Microarray analysis identified loperamide-induced changes in gene expression which were specifically associated with ivermectin-sensitive phenotypes in Collies possessing the ABCB1-1 Delta mutation. Gene pathway analysis further demonstrated that the altered genes are involved in immunological disease, cell death and survival, and cellular development. Thirteen genes, including CCL8 and IL-8, were identified. Collie dogs harboring ABCB1-1 Delta mutation which also exhibited toxicity toward ivermectin demonstrated systematic responses following loperamide treatment exhibited by altered expression of genes involved in immune and inflammatory signaling pathways. Genes such as CCL8 and IL-8 are potential biomarkers in whole blood that may predict the safety of loperamide in dogs with ABCB1-1 Delta mutation associated with ivermectin sensitivity. |
| Author | Zhu, M. Jones, Y. L. Myers, M. J. Yancy, H. F. Deaver, C. |
| Author_xml | – sequence: 1 givenname: M. surname: Zhu fullname: Zhu, M. organization: U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research, MD, Laurel, USA – sequence: 2 givenname: H. F. surname: Yancy fullname: Yancy, H. F. organization: U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research, MD, Laurel, USA – sequence: 3 givenname: C. surname: Deaver fullname: Deaver, C. organization: U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research, MD, Laurel, USA – sequence: 4 givenname: Y. L. surname: Jones fullname: Jones, Y. L. organization: U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research, MD, Laurel, USA – sequence: 5 givenname: M. J. surname: Myers fullname: Myers, M. J. email: michael.myers@fda.hhs.gov organization: U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research, MD, Laurel, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26471945$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1146/annurev.immunol.20.091301.131133 10.1016/S1359-6101(97)00022-1 10.1016/0092-8674(94)90212-7 10.3945/ajcn.110.001545 10.1189/jlb.72.5.847 10.1186/1742-2094-2-7 10.1097/00000542-200204000-00019 10.1124/dmd.107.018978 10.1172/JCI118699 10.2460/javma.233.6.921 10.1002/ddr.21227 10.2460/ajvr.2002.63.479 10.1006/scbi.1997.0068 10.1073/pnas.0402374101 10.1007/s000110050308 10.1124/dmd.115.063735 10.1016/S1074-7613(00)80165-X 10.1128/IAI.67.3.1471-1480.1999 10.1124/dmd.107.017624 10.1111/j.1365-2885.2004.00585.x 10.2460/ajvr.75.12.1104 10.1292/jvms.67.1103 10.1002/eji.200838660 10.1111/j.1939-1676.2004.tb00145.x 10.1128/IAI.72.9.5019-5026.2004 10.3389/fendo.2015.00029 10.1097/00008571-200111000-00012 10.1016/j.vetpar.2005.05.004 |
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| Snippet | This study evaluated the impact of the ABCB1‐1Δ mutation in Collies which exhibited toxicity toward ivermectin, on changes in gene expression when given the... This study evaluated the impact of the ABCB1-1Δ mutation in Collies which exhibited toxicity toward ivermectin, on changes in gene expression when given the... This study evaluated the impact of the ABCB 1‐1Δ mutation in Collies which exhibited toxicity toward ivermectin, on changes in gene expression when given the... This study evaluated the impact of the ABCB1-1 Delta mutation in Collies which exhibited toxicity toward ivermectin, on changes in gene expression when given... |
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| SubjectTerms | Animals ATP-Binding Cassette, Sub-Family B, Member 1 - genetics ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism Dog Diseases - blood Dog Diseases - chemically induced Dog Diseases - genetics Dog Diseases - metabolism Dogs Drug Hypersensitivity - veterinary Female Gene Expression Regulation - drug effects Gene Expression Regulation - immunology Inflammation - chemically induced Inflammation - genetics Inflammation - metabolism Inflammation - veterinary Ivermectin - adverse effects Loperamide - pharmacology Male Mutation |
| Title | Loperamide‐induced expression of immune and inflammatory genes in Collies associated with ivermectin sensitivity |
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