The ABCB1 Gene in Dogs
Author(s):
Cynthia Cole
Updated:
JUN 01, 2018
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All clinicians will be aware of ivermectin sensitivity in Collies, but what is generally not recognized is that the gene responsible is much more widespread than first thought; moreover the mutation can cause adverse reactions to many other drugs apart from ivermectin, as Cindy Cole explains.
Cynthia Cole
DVM, PhD, Dipl. ACVCP
Dr. Cole qualified from the College of Veterinary Medicine, University of Florida and began her career in academia before holding roles in several animal pharmaceutical companies. She joined Wisdom HealthTM (formerly Mars Veterinary) as R&D Director in 2014 and is currently General Manager for the company.
Key Points
- Many breeds of dog carry the ABCB1 gene mutation and can be susceptible to various drugs used routinely in veterinary medicine.
- Wherever possible such drugs should be avoided in dogs carrying the mutation, but if necessary the clinician should adjust the dosage after careful consideration of the factors involved.
Previously referred to as MDR1 (Multi-Drug Resistance), the ABCB1 gene codes for P-glycoprotein (P-gp), an ATPase transporter that moves small molecules (substrates) across the cell membrane. The importance of P-gp was underscored in 2001 when a mutation in the ABCB1 gene was identified as the cause of ivermectin sensitivity in Collies (1,2). Initially, the clinical significance of the mutation was thought to be limited to macrocyclic lactones, a drug class which includes ivermectin, milbemycin oxime, selamectin, and a number of other molecules commonly used as parasiticides. However, it is now recognized that there is a long list of P-gp substrates, many of which are commonly used in veterinary medicine (Table 1). The mutated ABCB1 gene results in production of a truncated protein, leading to altered handling of these medications, and clinical signs of toxicity occur when normally therapeutic doses are administered to dogs with one or two copies of the mutation. Various reports have implicated the mutation with toxicity to many different drugs, including loperamide (Figure 1) (3), acepromazine (4) and the chemotherapeutic agents vincristine, vinblastine, and doxorubicin (5).
Table 1. Drugs currently known to be substrates for P-glycoprotein.
Figure 1. Roxy developed neurological signs following administration of a “therapeutic” dose of loperamide. Subsequent genotyping revealed her to have two copies of the ABCB1 mutation.
What breeds are affected?
The mutation is thought to have originated in herding dogs in Britain in the 1800’s (6). Although today many of the herding breeds are commonly affected, the breed distribution of the mutation is not straightforward. Collies have the highest frequency of the mutation, with up to 75% of some populations carrying at least one copy (6). Other commonly affected breeds include a number of herding breeds, such as Australian Shepherds and McNabs. Genetic analysis reveals that most likely a single mutation occurred in a shared ancestor of the herding breeds. [...]
About
Affiliation of the authors at the time of publication
Wisdom HealthTM, Portland, OR, USA.
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