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Eur J Pharmacol. 2003 Jan 24;460(2-3):85-91.

MDR1-deficient genotype in Collie dogs hypersensitive to the P-glycoprotein substrate ivermectin.

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  • 1Laboratoire de Pharmacologie et Toxicologie, INRA-180 Chemin de Tournefeuille, BP 3, 31931 Toulouse Cedex 9, France.

Abstract

Multidrug resistance (MDR) phenotypes in cancer cells are associated with overexpression of the drug carrier P-glycoprotein. The antiparasitic drug ivermectin, one of its substrates, abnormally accumulates in the brain of transgenic mice lacking the P-glycoprotein, resulting in neurotoxicity. Similarly, an enhanced sensitivity to ivermectin has been reported in certain dogs of the Collie breed. To explore the basis of this phenotype, we analyzed the canine P-glycoprotein-encoding MDR1 gene, and we report the first characterization of the cDNA for wild-type (Beagle) P-glycoprotein. The corresponding transcripts from ivermectin-sensitive Collies revealed a homozygous 4-bp exonic deletion. We established, by genetic testings, that the MDR1 frame shift is predictable. Accordingly, no P-glycoprotein was detected in the homozygote-deficient dogs. In conclusion, we characterized a unique case of naturally occurring gene invalidation. This provides a putative novel model that remains to be exploited in the field of human therapeutics and that might significantly affect tissue distribution and drug bioavailability studies.

PMID:
12559367
[PubMed - indexed for MEDLINE]
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