MDR1-deficient genotype in Collie dogs hypersensitive to the P-glycoprotein substrate ivermectin.
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.
Roulet
Alain
A
Laboratoire de Pharmacologie et Toxicologie, INRA-180 Chemin de Tournefeuille, BP 3, 31931 Toulouse Cedex 9, France.
Puel
Olivier
O
Gesta
Stéphane
S
Lepage
Jean-François
JF
Drag
Marlene
M
Soll
Mark
M
Alvinerie
Michel
M
Pineau
Thierry
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D004247:DNA / Q000737:chemistry / Q000235:genetics; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D004285:Dogs; D018432:Drug Resistance, Multiple / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007559:Ivermectin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018076:DNA, Complementary; D007559:Ivermectin; D004247:DNA