Today's Veterinary Nurse

SEP-OCT 2017

Practical, peer reviewed, state-of-the-art companion animal nursing and technical educational articles with CE. Promotes better health for animals and career growth and development for veterinary technicians and veterinary assistants.

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PEER REVIEWED 58 | TODAY'S VETERINARY TECHNICIAN | September/October 2017 P-glycoprotein In normal dogs, P-glycoprotein functions as a pump, moving potentially toxic compounds out of the central nervous system (CNS). It also transports substrate drugs across cell membranes and out of the body. This occurs at the level of biliary canaliculi, intestinal epithelial cells, and renal proximal tubular epithelial cells. Prescribed medications can therefore behave in a predictable manner when proper dosing instructions are followed. However, when the MDR1 mutation is present, P-glycoprotein is severely truncated, rendering it ineffective. Substrates for P-glycoprotein, including many common medications, remain in the CNS at toxic levels or are otherwise incorrectly metabolized or excreted. This can lead to severe and potentially fatal adverse drug reactions. Additionally, further research has revealed that P-glycoprotein plays a role in the regulation of the hypothalamic-pituitary-adrenal axis. 2 In dogs that are homozygous for the MDR1 mutation (BOX 1) , this important hormonal feedback system does not function normally, causing lower cortisol levels. The effects become apparent under periods of high stress, such as illness or extreme physical activity. These dogs may respond poorly to such increased energy demands and exhibit evidence of relative adrenal insufficiency. In some cases, physiologic doses of corticosteroids are indicated. AFFECTED BREEDS In the 1980s, when new parasiticides, such as ivermectin, were introduced, collie owners and veterinarians began reporting adverse drug reactions. Dog owners attempted to identify which dogs were most likely to have a reaction by using phenotypic qualities, such as coat color or markings. A common adage at the time was "white feet, don't treat," meaning that dogs with white feet were thought to be more susceptible to ivermectin toxicity. Because of early reports of ivermectin toxicity in collies, that breed became the early model for researchers to discover more about this genetic mutation. It became clear that not only collies, but also other herding-breed dogs, possessed this abnormal genetic code. A Herding Dog Gene By using advanced evolutionary genetic techniques, scientists traced the history of this mutation over time. 3 It first appeared in a herding dog in Great Britain in the late 19th century, before the collie breed even originated. This anonymous dog may have possessed some desirable feature or skill, which meant that it passed its genes on to numerous descendants. Unknown to generations of breeders, the MDR1 mutation was passed on as well. Eventually, dog breeds became more clearly defined. As new breeds developed from older ones, the genetic heritage followed. By analyzing how far back in the canine family tree a breed broke off from the foundation stock, geneticists can predict which descendant breeds potentially carry the mutation (BOX 2) . The MDR1 mutation has been identified in 10 herding breeds, 2 sighthound breeds, and herding- breed mixed dogs (TABLE 1) . 4 Collies have one of the highest frequencies—approximately 70% are homozygous or heterozygous for the mutation. Australian shepherds and Shetland sheepdogs are also MDR1 Genetic Testing: What You Need to Know Just like people, dogs inherit 1 copy of a gene from the father and 1 from the mother. A complete genome therefore contains 2 copies of each gene (1 from each parent). If a dog inherits 1 normal copy of the gene and 1 mutant copy, the dog is considered heterozygous for the mutation and is reported as mutant/normal. A dog with 2 abnormal copies is called homozygous, or mutant/ mutant. A dog that does not carry any copies of the mutation is referred to as normal/normal. It is confusing to refer to genetic results as "positive" or "negative" because the meaning in some contexts can be ambiguous. Similarly, the MDR1 mutation is a dominant genetic trait, so the use of the word "carrier" for heterozygous dogs is incorrect. Both heterozygous and homozygous dogs can show drug toxicosis when given P-glycoprotein substrates. BOX 1 Inheritance of MDR1 Mutation TABLE 1 Breeds Affected by the MDR1 Mutation 4 BREED APPROXIMATE FREQUENCY (%) Collie 70 Long-haired whippet 65 Australian shepherd 50 Australian shepherd, mini 50 McNab collie 30 Silken windhound 30 English shepherd 15 Shetland sheepdog 15 German shepherd 10 Herding-breed cross 10 Mixed breed 5 Old English sheepdog 5 Border collie <5

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