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Loperamide‐induced expression of immune and inflammatory genes in Collies associated with ivermectin sensitivity
Author(s) -
Zhu M.,
Yancy H. F.,
Deaver C.,
Jones Y. L.,
Myers M. J.
Publication year - 2016
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1111/jvp.12268
Subject(s) - loperamide , biology , gene , mutation , ivermectin , mutant , gene expression , microarray , microarray analysis techniques , fold change , microbiology and biotechnology , genetics , pharmacology , medicine , diarrhea , zoology
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.