title: Loperamide-induced expression of immune and inflammatory genes in Collies associated with ivermectin sensitivity.
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.
authors.affiliation: U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research, Laurel, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zhu
authors.affiliation: U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research, Laurel, MD, USA.
authors.forename: H F
authors.initials: HF
authors.lastname: Yancy
authors.affiliation: U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research, Laurel, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Deaver
authors.affiliation: U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research, Laurel, MD, USA.
authors.forename: Y L
authors.initials: YL
authors.lastname: Jones
authors.affiliation: U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of Research, Laurel, MD, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Myers
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004283:Dog Diseases / Q000097:blood / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D004342:Drug Hypersensitivity / Q000662:veterinary*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000662:veterinary*; D007559:Ivermectin / Q000009:adverse effects*; D008139:Loperamide / Q000494:pharmacology*; D008297:Male; D009154:Mutation
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008139:Loperamide; D007559:Ivermectin