Frequency of the Mutant MDR1 Allele in a Sample of Shepherd Dogs in France: Correlation with French Pharmacovigilance Data
The multidrug resistance gene (MDR1) produces P-glycoprotein (P-gp) that belongs to the ATP Binding Cassette protein superfamily. P-gp is involved in the active cellular efflux of a large number of drugs and transports many structurally and pharmacologically unrelated hydrophobic compounds including macrocyclic lactones, anticancer agents, immunosuppressive agents, steroid hormones, calcium channel blockers, β-blockers, cardiac glycosides, antibiotics ... In the central nervous system (CNS), P-gp is found in the capillary endothelial cells that form the blood brain barrier. So, the role of P-gp is particularly important for the protection against accumulation in the CNS of macrocyclic lactones (or other P-gp substrate drugs) and its subsequent neurotoxicity. P-gp is also disposed on the biliary canicular membrane of hepatocytes and on the apical side of enterocytes, and is a key player in both biliary and intestinal secretion of P-gp substrate drugs.
A 4-bp deletion mutation of MDR1 gene was described in ivermectin-sensitive collies. This mutation generates a premature stop codon, preventing synthesis of the complete and active protein product.
Between June 2003 and December 2007, 264 dogs (97 Australian shepherds, 81 collies and 86 white German shepherds) living in France were tested in Antagene laboratory or in Washington State University Laboratory by PCR for genotyping MDR1. Only 13.6 % of the collies studied were homozygous for the normal allele (normal), 40.7% were heterozygous (carrier), and 33.3% were homozygous for the mutant allele (affected). For Australian shepherds and white German shepherds, respectively, 9.3% and 3.5% of tested dogs were affected; in addition 43.3% and 17.4% were carrier. Some of the tested dogs were clinically sensitive to macrocyclic lactones or loperamide; all of the dogs with signs of toxicosis were homozygous for the mutant allele or heterozygous. Macrocyclic lactones and loperamide were prescribed at dosages that cause no adverse effects in normal dogs. In purebred or mixed dogs of these breeds, veterinarians should perform a test before prescribing any P-substrate drug to avoid toxicosis in affected or carrier dogs.