Our furry friends need to take icky medicinal treatments, as well. Understanding their genetic predisposition to drugs can provide them with the comfort they oh-so-deserve.
Gene Dosage is a monthly column by Janan Arslan that finds out what genome science is uncovering about each individual's unique response to drugs and pharmaceuticals. Janan is a graduate student and pharmacogenomics researcher with a keen interest in personalised medicine.
This month’s column was inspired by my two kittens, one of whom is currently curled up on my lap, while the other is purring and head-butting me as I write this. Too cute for words, right? As adorable as they are, kittens require a lot of attention and care. For months, I’ve been running around tirelessly after them as they jump from one place to another. I’ve made several trips to the veterinary clinic for their vaccinations and spaying (and, on one unfortunate occasion, to treat a tummy bug ‒ a lesson for Oreo not to eat everything in sight).
I’ve realised that at no point did the veterinary nurses elaborate on the types of medications they would administer and how these medications would affect my cats. Rather, it was mentioned in passing, with a reassurance not to worry. Naturally, scientific curiosity got the better of me, and I had to see for myself. So this piece is for me, and for all you animal lovers out there.
While pharmacogenomics has more or less established itself in human medicine, the same cannot be said of veterinary medicine, where its use is considered feasible, but literature on the subject is very limited. We know very little about the genetic heritability of drug response amongst animals, but breed-specific drug responses across a range of species (including cattle, sheep, chickens and pigs) show that genetics most likely plays a part in drug efficacy. This breed-specific response is akin to human responses to drugs: certain human sub-populations have particular genetic variants that can make them more vulnerable to adverse events.
A perfect example of these breed-specific responses is the difference between mongrel dogs and beagle dogs for the anti-epileptic drug phenobarbitone and the non-steroidal anti-inflammatory drug (NSAID) naproxen. Compared to mongrel dogs, beagles have a shorter elimination half-life ‒ the time required for a drug to lose half its original concentration. This means that the drug wears off faster in beagles than in mongrel dogs. Similarly, ibuprofen-related gastrointestinal ulceration is low for labrador retrievers but very high for German shepherds.
Remember my column about thiopurine methyltransferase (TPMT) deficiency in humans? The same is applicable for dogs. In humans, genetic variants can lead to low TPMT activity. TPMT metabolises thiopurines, which range from immunosuppressants to cancer drugs. Low TPMT activity increases the chances that adverse events, like bone marrow toxicity, will occur.
In dogs, azathioprine is similarly used to treat immune-related diseases, inflammatory bowel diseases and dermatological diseases. Among dogs, a total of nine genetic variants have been identified that contribute to varied TPMT activity, six of which explain 40% of variability across all breeds of dogs. Breeds such as giant schnauzers have significantly lower TPMT activity, while Alaskan malamutes have higher TPMT activity. This suggests that schnauzers are susceptible to adverse events, while malamutes may not gain any benefit from the medication.
As in dogs and humans, cats with immune-mediated diseases can also benefit from azathioprine. However, the medication is less commonly used in cats, since they have a high incidence of myelosuppression ‒ a reduction of bone marrow which results in lower levels of white and red blood cells and platelets, and therefore lowered immunity. Cats have low TPMT activity, which most likely explains their sensitivity to thiopurine treatments. Other animals in which low TPMT activity has been noted include horses and mice. As testing TPMT activity is well-established among humans, perhaps it could become a good starting point for these animals.
In addition to azathioprine, domestic cats show sensitivity to drugs such as paracetamol (acetaminophen) and aspirin. One of the genes responsible for processing acetaminophen and aspirin is UGT1A6.
In an earlier column, I touched on the UGT family. To quote myself: “Genes that belong to the UGT family code for an enzyme that performs glucuronidation, a chemical reaction in which glucuronic acid, a derivative of glucose, is conjugated (attached) to substances.” By attaching itself to a substance, glucuronic acid converts a toxic substance into a non-toxic one. So it’s really a detoxification process.
Aspirin is converted to its metabolite, salicylic acid, which can then either be metabolised by a CYP gene or undergo glucuronidation by UGT1A6. Acetaminophen has three potential pathways, one of which is glucuronidation into its non-toxic form. In cats, there appears to be a lack or poor expression of UGT1A6. The gene is considered to be a “pseudogene”, containing multiple deleterious mutations. This accounts for the slow clearance of these medications, making cats incredibly sensitive to these drugs and experiencing greater side effects than dogs or other mammals.
In humans, the gene CYP2D6 is considered the most valuable for testing, as a large number of drugs use CYP2D6 as part of their metabolic pathways. For dogs, the equivalent would be CYP2D15, which metabolises drugs including celecoxib (a NSAID), dextromethorphan (a cough suppressant), and imipramine (an anti-depressant). Variants identified for this gene include CYP2D15*2, CYP2D15*3, CYP2DWT2 and CYPD15 delta. A celecoxib study, which involved 242 beagles, showed that 45% of the dogs had normal metabolism, while 53% had poor (slow) metabolism (with 2% uncertain). From my perspective, that’s a huge number of poor responders; in humans, by comparison, poor metabolisers (for CYP2D6) account for only 5-10% of total responders, depending on ethnicity.
Finally, a note about chocolate toxicity in pets. The chemical in chocolate that is responsible for pet poisoning is theobromine. While the amount of theobromine in chocolate is small enough for us humans to consume safely (although we, too, have a small risk of theobromine poisoning), our pets are not as fortunate. They metabolise theobromine very slowly, and are less efficient at detoxifying it.
The difference in metabolic activity between humans and animals has been attributed to the presence of CYP genes in humans (specifically CYP2E1 and CYP1A2). That said, a study on beagles (yet again) suggests that CYP1A2 genetic variants in dogs cause elevated levels of theobromine (and an insufficient ability to clear the chemical in a timely manner) compared to dogs with normally functioning CYP1A2.
There appear to be many parallels between drug metabolism in humans and in various other animals. So perhaps it’s not too much of a stretch to start seriously thinking about clinical applications of pharmacogenomics in veterinary science.
Edited by Andrew Katsis and Ellie Michaelides