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

Autor: Thierry Pineau, Soll Mark D, Michel Alvinerie, Jean-François Lepage, Stéphane Gesta, Marlene Drag, Olivier Puel, Alain Roulet
Přispěvatelé: Inconnu, Unité de recherche Pharmacologie-Toxicologie (UPT), Institut National de la Recherche Agronomique (INRA), Département Santé Animale (DEPT SA)
Rok vydání: 2003
Předmět:
Male
DNA
Complementary
Genotype
040301 veterinary sciences
[SDV]Life Sciences [q-bio]
Blotting
Western
Molecular Sequence Data
Drug resistance
medicine.disease_cause
Polymerase Chain Reaction
0403 veterinary science
03 medical and health sciences
Dogs
Sequence Homology
Nucleic Acid
medicine
Tumor Cells
Cultured
Animals
Humans
ATP Binding Cassette Transporter
Subfamily B
Member 1
Amino Acid Sequence
ComputingMilieux_MISCELLANEOUS
Alleles
030304 developmental biology
P-glycoprotein
Pharmacology
Genetics
0303 health sciences
Mutation
Ivermectin
biology
Base Sequence
Sequence Homology
Amino Acid
Collie
Neurotoxicity
04 agricultural and veterinary sciences
DNA
Sequence Analysis
DNA
medicine.disease
Molecular biology
Phenotype
Drug Resistance
Multiple
3. Good health
Multiple drug resistance
biology.protein
Female
Sequence Alignment
Zdroj: European Journal of Pharmacology
European Journal of Pharmacology, Elsevier, 2003, 460 (2-3), pp.85-91. ⟨10.1016/S0014-2999(02)02955-2⟩
ISSN: 0014-2999
Popis: 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.
Databáze: OpenAIRE
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