Dataset Information

Novel insertion mutation of ABCB1 gene in an ivermectin-sensitive Border Collie.

ABSTRACT: P-glycoprotein (P-gp) is encoded by the ABCB1 gene and acts as an efflux pump for xenobiotics. In the Border Collie, a nonsense mutation caused by a 4-base pair deletion in the ABCB1 gene is associated with a premature stop to P-gp synthesis. In this study, we examined the full-length coding sequence of the ABCB1 gene in an ivermectin-sensitive Border Collie that lacked the aforementioned deletion mutation. The sequence was compared to the corresponding sequences of a wild-type Beagle and seven ivermectin-tolerant family members of the Border Collie. When compared to the wild-type Beagle sequence, that of the ivermectin-sensitive Border Collie was found to have one insertion mutation and eight single nucleotide polymorphisms (SNPs) in the coding sequence of the ABCB1 gene. While the eight SNPs were also found in the family members' sequences, the insertion mutation was found only in the ivermectin-sensitive dog. These results suggest the possibility that the SNPs are species-specific features of the ABCB1 gene in Border Collies, and that the insertion mutation may be related to ivermectin intolerance.

SUBMITTER: Han JI

PROVIDER: S-EPMC2998746 | biostudies-other | 2010 Dec

REPOSITORIES: biostudies-other

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Novel insertion mutation of ABCB1 gene in an ivermectin-sensitive Border Collie.

Han Jae-Ik JI Son Hyoung-Won HW Park Seung-Cheol SC Na Ki-Jeong KJ

Journal of veterinary science 20101201 4

P-glycoprotein (P-gp) is encoded by the ABCB1 gene and acts as an efflux pump for xenobiotics. In the Border Collie, a nonsense mutation caused by a 4-base pair deletion in the ABCB1 gene is associated with a premature stop to P-gp synthesis. In this study, we examined the full-length coding sequence of the ABCB1 gene in an ivermectin-sensitive Border Collie that lacked the aforementioned deletion mutation. The sequence was compared to the corresponding sequences of a wild-type Beagle and seven ...[more]

PMID: 21113104

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Project description:Alcohol use disorder (AUD) has a major national impact, affecting over 18 million people, causing approximately 88,000 deaths, and costing upward of $250 billion annually in the United States. Unfortunately, FDA-approved AUD pharmaceuticals are few, and clinical benefits are mostly ineffective in patients suffering from AUD. Therefore, the identification of novel targets and/or innovative methods for the development of safe and effective medications represents a critical public health need. Previously, we reported that avermectin compounds (ivermectin [IVM] and moxidectin [MOX]) significantly reduced ethanol intake in male and female mice. However, avermectin compounds are readily effluxed by P-glycoprotein (Pgp/ABCB1) in the blood-brain barrier (BBB), resulting in reduced retention time by the drugs in the central nervous system (CNS). As such, the doses of IVM or MOX and the time frame for significant reductions of ethanol intake are not ideal. Here we evaluate a novel combinatorial strategy involving IVM and tariquidar (TQ), a third-generation efflux inhibitor of Pgp, to reduce the dosing necessary for improving alcohol (ethanol) consumption behavior. We tested male C57BL/6J mice using a two-bottle choice study to evaluate ethanol consumption and preference. We found that injecting 10 mg/kg of TQ 30 min prior to IVM resulted in a five-fold improvement in the efficacy of IVM (dosed at 0.5 mg/kg), resulting in a significant reduction in ethanol intake and preference. Notably, the reduction by IVM was well tolerated, and no adverse effects were identified when tested at doses ranging from 0.50 mg/kg to 2.0 mg/kg. Collectively, our findings indicate that IVM, in combination with TQ, increases its efficacy in the CNS for reducing ethanol consumption. This work demonstrates a novel combinatorial drug strategy that allows new opportunities for drugs with poor CNS retention, such as IVM, to demonstrate improved potency and potentially improved safety.

Dataset Information

Novel insertion mutation of ABCB1 gene in an ivermectin-sensitive Border Collie.

Publications

Novel insertion mutation of ABCB1 gene in an ivermectin-sensitive Border Collie.

Similar Datasets

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