One animal’s cure can be another animal’s poison. Take aspirin – it’s one of the most popular drugs on the market and we readily use it as a painkiller. But cats are extremely sensitive to aspirin, and even a single extra-strength pill can trigger a fatal overdose. Vets will sometimes prescribe aspirin to cats but only under very controlled doses.
The problem is that cats can’t break down the drug effectively. They take a long time to clear it from their bodies, so it’s easy for them to build up harmful concentrations. This defect is unusual – humans clearly don’t suffer from it, and neither do dogs. All cats, however, seem to share the same problem, from house tabbies to African lions.
Now, Binu Shrestha from the Tufts University School of Medicine has found that cats may have developed their strange sensitivity because of their lifestyle as specialist hunters. Their penchant for meat could have ultimately turned aspirin into their kryptonite.
Our livers break down aspirin using a protein called UGT1A6, encoded by a gene of the same name. In 1997, Michael Court, who led Shrestha’s study, showed that the cat version of this protein is barely produced in the liver. Three years later, he found out why – the cat genome has a broken version of UGT1A6. The gene has been riddled with crippling mutations that prevent it from producing a working protein, like a recipe with missing and garbled steps. In technical terms, it’s a “pseudogene”.
This is an old problem. Shrestha looked at the gene in 18 species of cat, from cheetahs to servals to tigers, and found that all of them shared the same four crippling mutations. Several lineages had accumulated more. The common ancestor of all modern cats must have been just as sensitive to aspirin (or more realistically, similar natural compounds) than our house cats.
But this problem isn’t limited to cats. Shrestha checked the state of UGT1A6 in other carnivores, and found two other species – the brown hyena and the northern elephant seal – that also had busted versions. (If you own either species as a pet, don’t give them aspirin. Also, what is wrong with you?)
The gene was active and serviceable in other groups of meat-eaters, including the other three hyenas, dogs, bears, mongooses and racoons. What sets the cats, the seal and the brown hyena apart? Shrestha thinks it’s their diets. These species are all “hypercarnivores”, meaning that meat makes up more than 70% of their food. By comparison, bears and dogs are “mesocarnivores”, meaning that they eat some plant food too.
Like many other “detoxifying” proteins, UGT1A6 evolved to help animals cope with the thousands of dangerous chemicals in the plants they eat. For animals that eat plants, even on an irregular basis, these genes are a boon. Individuals with broken copies would be forced into narrower diets and lose out to those with working copies.
But if an animal’s menu consists largely of meat, it has little use for these anti-plant defences. The genes are dispensable. Individuals with broken versions can survive just as well as those with working ones, so the broken genes spread through the population. In this way, the ancestral cats gradually built up mutations that disabled their UGT1A6 gene. Evolution is merciless that way – it works on a “use it or lose it” basis.
UGT1A6 isn’t the only gene that’s gone through this fate. Cats also have low levels of amylase in their saliva, and enzyme that starts breaking down carbohydrates. And unlike many other mammals, they don’t have a sweet tooth because their copy of Tas1r2 – a gene involved in taste –is also a pseudogene. Both events might also have been the result of their move away from plant foods.
That’s not the whole story. Other hyenas, mongooses and weasels also count as hypercarnivores, and their copies of UGT1A6 work just fine. This means that a meat-heavy diet might predispose animals to inactivating their copies of UGT1A6, but it isn’t the only factor behind the gene’s downfall. Something else must have influenced the loss of this gene in the cats, brown hyena and northern elephant seal, but not in their kin. And Shrestha has an idea what that might be.
Modern cat families evolved from a common ancestor around 11 million years ago. Before then, there’s a bizarre lack of cat fossils – a so-called “cat gap” that lasted from 23 to 17 million years ago. It’s possible that during that time, cats passed through a “genetic bottleneck”. Their populations were small and any mutations within the surviving few were passed on to their descendants, including the faulty version of UGT1A6. It’s probably no coincidence that the northern elephant seal has also recently gone through a similar bottleneck.
Reference: Shrestha, B., Reed, J., Starks, P., Kaufman, G., Goldstone, J., Roelke, M., O’Brien, S., Koepfli, K., Frank, L., & Court, M. (2011). Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory PLoS ONE, 6 (3) DOI: 10.1371/journal.pone.0018046
More on cats:
March 29th, 2011 at 11:08 am
“(If you own either species as a pet, don’t give them aspirin. Also, what is wrong with you?)”
LOL, massive LOL!
Very productive comment, I know. Wait, I have one more:
“It’s probably no coincidence that the northern elephant seal has also recently gone through a similar bottleneck”
I see what you mean, but readers unfamiliar with genetic drift may be confused – it almost sounds like elephant seals had a bottleneck *because* of the faulty version of the gene, instead of the contrary (which is obvious to me, but some may be confused)
March 29th, 2011 at 4:07 pm
I’ve actually wondered why this is.
Thanks for informing me.
March 29th, 2011 at 5:10 pm
Why must I be tarred with the epithet “Loony” just because I have a pet northern elephant seal? {/montypython}
-mark.
March 29th, 2011 at 9:49 pm
This reminds me of a fundamental evolutionary complication of civilization – the more civilized our environment, the less evolutionary pressure on individual genetic lines – for example, with orthodontics becoming more and more popular, it is more difficult for prospective mates to judge the ‘tooth-fitness’ of an individual. So that individual reproduces, and the genetics of bad teeth are propagated. This is true of many genetic flaws. So, as a result, as time goes on the human population (and the population of other species such as dogs and cats) could become ever more unfit. Of course, the converse could also happen – the rise of genetically engineered children. (Which reminds me of “Last and First Men” by Olaf Stapledon.)
March 30th, 2011 at 3:16 am
the elephant seal population crash (bottle-neck) is pretty recent, I wonder if it’s possible to get ancient DNA from pre-bottle neck skins and test their gene status? It would be amazing if we could witness a gene change like this within historical rather than evolutionary timescales.
Also, might there be some cost to making proteins that aren’t used which makes their loss adventageous, over and above “don’t use it, loose it”?
March 30th, 2011 at 3:51 am
I once asked Deborah Blum this question, but clearly it’s not just a poison issue. Thanks, Ed. I’m pleased to say that I understand this now, despite being only an amateur biologist.
March 30th, 2011 at 1:02 pm
Also, as a quick note, do not ever give cats acetaminophen (Tylenol) as it can be rapidly fatal. Cats can’t metabolize the drug properly and the toxic metabolites can kill a cat. This is something that is often seen in animal ERs so I just wanted to put it out there.
March 30th, 2011 at 2:55 pm
I often take issue with how people refer to evolved characteristics. For example, this article states “Like many other “detoxifying” proteins, UGT1A6 evolved to help animals cope with the thousands of dangerous chemicals in the plants they eat. For animals that eat plants, even on an irregular basis, these genes are a boon. Individuals with broken copies would be forced into narrower diets and lose out to those with working copies.”
The structure of this statement suggests a directed activity. In this case it is “UGT1A6 evolved…”, but I suggest nothing of the sort happened.
Is it not more appropriate to indicate that the development of UGT1A6 in animals provided a means to better cope with certain naturally occuring chemicals instead of suggesting that “animals” sat around and decided they need to start creating this protien to do so?
March 30th, 2011 at 3:54 pm
> This reminds me of a fundamental evolutionary complication of civilization – the more civilized our environment, the less evolutionary pressure on individual genetic lines
Except this is exactly backwards! Evolution sped up by two orders of magnitude with the invention of agriculture and civilization. Humans were optimized for a hunter gather lifestyle, and when thrown into a radically new environment our genes were way out of equilibrium (and still are). As a result, evolution has gone into overdrive — the slope of the fitness landscape is quite high right now, and will continue to be until the population finally settles in a new local optimum.
March 30th, 2011 at 4:58 pm
I don’t like thats you call cat’s inability to survive aspirin a “defect”? Are we defective because we can’t crack bones? There are bonuses get from our genetic legacy of being omnivorous primates, that doesn’t make cats “defective”.
Also, a dose is called an overdose when it has undesirable effects, but you can’t “trigger an overdose” with a pill. Either the dose is an overdose or not depending on its effects.
“This defect is unusual – humans clearly don’t suffer from it, and neither do dogs.”
It is not unusual that an animal reacts unfavorably to something specifically develop to help cope with headaches in humans. I would argue that the unusual animals are the dogs. In addition, they can’t cope with chocolate! that’s what I call a defect. Sorry, I am a cat person, just in case you didn’t notice
March 31st, 2011 at 3:25 am
@ Paul:
“Evolution sped up by two orders of magnitude with the invention of agriculture and civilization”
Uhm… can you provide some reference please? It sounds strange to me & it’s definitely interesting, so I’d like to check if it is true and in case yes learn more about it…
March 31st, 2011 at 8:36 am
I believe this research is flawed. The assumption here is that the cats had a meat dominant diet before the mutation, which allowed the mutation of the gene to go “unnoticed” (or don’t use it you lose it I think the article claims). First off, evolution has nothing to do with a don’t use it you lose it. It could very well be the case that the cat had a more plant centered diet, like the dog, and then came about the mutation. This mutation shifted the animals preference to a more meat dominant diet. Of course it could be the case that the diet shift came first, but I do not think the research adds evidence to this hypothesis. Finally, the two events could be completely seperate. Just because X & Y occur shortly after one another does not at all imply that x causes y or vice versa..
But i’ll be sure not to feed my elephant seal aspirin…
March 31st, 2011 at 11:31 am
Discover needs a good editor who can flag an article for assumptions and bias that ought to be re-thought by the writer before publication. Many instances here; for example, repeatedly using the word “defect” in relation to cats in comparison to humans (and other animals) is misleading. Science writing should not mislead (that is, if Discover considers what it does as “science writing,” which I doubt it does). Also, what is meant by “four crippling mutations?” I think this might have some connection to “riddled with defects,” but the connection is completely defective. In any case, the dramatization (“crippling?,” “riddled?”) in those two examples reveals and promotes a strong bias. A little dramatization is fine, but it needs to be done more carefully.
Furthermore, I really do not need lame similes like “turned aspirin into their kryptonite” to help me understand the danger of aspirin to a cat. It’s an unnesessary distraction; the article well states the danger already. No doubt this author would also call chocolate dogs’ kryptonite. Say, let’s have an article that lists every animal’s “kryptonite.” Perfect for Discover.
March 31st, 2011 at 12:56 pm
What a facinating post! Cats are certainly specialists, but there really isn’t anything “broken” about them. Most of us (who study cats and other small carnivores) like to note that they stopped evolving early on; that their body form achieved the perfect balance and stopped there. This is why they have so many fewer genes than dogs (insert cruel anti-dog joke here).
In our vet nurse pharmacology class, the professor had to stop and say, every few days, “cats are weird”. Because so many drugs are toxic to them. Read the book Your Cat by Dr. Elizabeth Hodgkins to see how the pet food industry has bilked consumers by tossing grains into cat food (which they can’t digest) and then creating phony formulas to solve the “illnesses” allegedly caused by nature but more likely caused by inflammation because cats evolved digestive tracts that cannot handle grains.
But again – look at any cat. Sleek, efficient, muscular hunting, stalking and killing machine. In my mind, there’s nothing broken about it.
I should read more about this, but I think that losing certain genes may have been necessary or at least benign in the cat world. Domestic cats have evolved some unique traits but wild cats should not have any reason to come into contact with aspirin or any variation (as you already noted) but cat divergence and domestic cat adaptations are facinating. As Hodgkins notes, if they evolved to eat grains, they would be competing with the mice, instead of killing them. Which is why we domesticated them to begin with.
Since they evolved to kill much larger prey than themselves, cats only need to be in an area with other living things, not to worry about what toxins they can handle.
April 1st, 2011 at 1:10 am
So, is there any home remedy for pain, that is SAFE for cats?
April 1st, 2011 at 6:39 pm
@Tina – the short answer is no. But don’t despair, there are solutions. If a cat has arthritis, glucosamine-chondroiton can help them. (We bought the vegetarian option and I’ll let you know if it works – some seafood has thiaminase which breaks down thiamine in cats, and fish is top of the food allergy list for cats). Exercise, flax seed oil (which reduces inflammation) and heat can help kitties feel better. Ask the vet first, of course. Buprinex and dexamethasone are good for cats with severe problems like cancer and some vets will give you a decent supply.
April 1st, 2011 at 7:38 pm
This is cool. I find stuff like this interesting. Which is why I read I guess…
April 6th, 2011 at 9:14 pm
@ William and Emmy: not the cat [or the elephant seal of course] is broken or has a defect, just its gene UGT1A6 is / has
.
By the way, the most famous aspirin-”producing” plant is the willow. Without it, we even didn’t have aspirin at all …
April 18th, 2011 at 10:34 am
@Emmy: I find your recommendations quite funny. Exercise. My problem would be how you prevent a cat from exercising, except by giving it an unnatural diet. If it is being fed a bad diet obviously it will not feel well, and will not feel like doing anything. Also Flax Seed Oil to a CAT. Why subject it to more plant toxins. This article was telling how cats cannot handle plant toxins and then you want to feed it toxins because some rat study showed inflammation reduction. Cat is not a rat, not by a long shot. Why not feed the cat some sardines, it will provide enough Omega3s for counteracting inflammation. It will also provide it with some good food. Also get some live animals that it can hunt. Maybe it is getting sick of not being able to hunt anything. I know you might find these ideas horrible. But will somebody please think of the kitten. You tamed it, you are responsible for its well being. If you don’t provide a proper environment for it, then you are to blame.
April 18th, 2011 at 3:28 pm
@ anand srivastava –
Anand, please take some animal science courses so you can better understand cat nutrition. Flaxseed oil is used in many pet foods and is not toxic. There is some debate about how much of the nutrients can be absorbed.
There are several reasons not to use fish for cats:
1. Fish contains thiaminase, the enzyme which breaks down thiamine (B1). Cats deficient in this nutrient may exhibit vomitng, lethargy and a slow heartbeat. B1 is essential to a cat’s nervous system and cardiovascular health. Cooked fish is free of harmful thiaminase. But for god’s sake, do not feed raw sardines to your cat.
2. The most common food allergy in cats is fish. They develop “chin acne”, which can turn into a staph infection.
3. Larger fish can be contaminated with mercury. Certain types of algae are being studied as better omega 3s in humans, so I am looking into that in cats.
Cats may not exercise for a number of reasons. If the cat is overweight (which many cats are these days), they need to get moving to save their cardiovascular system and they need to lose weight. If they are declawed, that can also cause arthritis. It all depends on why they are uncomfortable.
August 16th, 2011 at 11:48 am
Emmy – Your points on feline nutrition are well taken. Our cat has chronic renal failure and will probably not be with us much longer. We are managing her condition through a combination of subcutaneous fluid treatments and the best food we can buy. One of our enduring regrets is that, for most of her life, we simply didn’t know just how bad commercial pet food really is. The manufacturers have brainwashed consumers for decades with deceptive advertising campaigns, but many of us have seen the light and market pressure is encouraging a proliferation of grain-free choices for both cats and dogs.
You mention glucosamine and chondroitin. The best-known supplement, of course, is Cosequin for Cats. As I understand it, its glucosamine is derived from shellfish, and the product is flavored with tuna. Do you think there is a significant danger of a thiaminase issue here – enough to use something else?
December 2nd, 2011 at 7:33 am
“If you own either species as a pet, don’t give them aspirin. Also, what is wrong with you?”
Hahahahahahahaaaahaha………I laughed so hard that I actually did roll on the floor and cried too!
Hahahahahahaha!!!!!