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

Eur J Pharmacol. 2003 Jan 24;460(2-3):85-91. doi: 10.1016/s0014-2999(02)02955-2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Alleles
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Blotting, Western
  • DNA / chemistry
  • DNA / genetics
  • DNA, Complementary / chemistry
  • DNA, Complementary / genetics
  • Dogs
  • Drug Resistance, Multiple / genetics
  • Female
  • Genotype
  • Humans
  • Ivermectin / metabolism
  • Ivermectin / pharmacology*
  • Male
  • Molecular Sequence Data
  • Polymerase Chain Reaction
  • Sequence Alignment
  • Sequence Analysis, DNA
  • Sequence Homology, Amino Acid
  • Sequence Homology, Nucleic Acid
  • Tumor Cells, Cultured


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • DNA, Complementary
  • Ivermectin
  • DNA

Associated data

  • GENBANK/AF045019
  • GENBANK/AF269224
  • GENBANK/AJ419568