Monday, March 27, 2017

Differential Mammalian Toxicity: Why Do Some Human Foods Kill Dogs?

I've been contemplating this post for a while, but it can be seen as another angle on my recent post on the challenges of drug discovery, so it finally left the mental queue.  We often use other mammalian species in drug development to predict human toxicity.  We know animals aren't the same as people, but lacking a better alternative that's what we do.  Now, as regular readers know I keep company with a dog, and that sometimes has me wondering: how well do we understand the cases of things we can eat but which are dangerous for our canines?

When I say how well do we understand, I want to know at every level.  To give a simple example, we do know in great detail why we experience a burning sensation upon eating hot peppers whereas birds show no reaction.  We experience this because the active compound, capsaicin, binds to and activates the ion channel TRPV1 which plays a role in sensing heat and pain.  So it isn't some metaphor to say a Scotch bonnet pepper is so hot it hurts; the capsaicin is essentially chemical heat and pain.  However, in birds the TRPV1 channel has an amino acid change relative to mammal which renders it insensitive to capsaicin.

As as aside, this property of mammals sensitive, birds insensitive, is sometimes used to advantage. -- at least sometimes it works  Our previous house had a deck that was perfectly placed for a bird feeder, but we had a lot of trouble with squirrels and chipmunks raiding it.  So I tried once dosing the seed with hot pepper powder, which you can find in the bird feed section of a store.  I wish I could get tissue from those rodents to examine them for TRPV1 polymorphisms, as they didn't care a bit - but my eyes took a beating from the dust inevitably kicked up during loading operations.  On the other hand, this issue did once lead to an amazing treat -- at nightfall I watched a flying squirrel glide to a landing on the deck so it could raid the feeder!

Back to dogs.  Perhaps the most notorious example of a human food which can kill a dog is chocolate.  A friend once posted on social media a plea for advice, as her adult labrador retriever has inhaled a full batch of chocolate chip cookie dough when her back was turned.  I did a quick search online and came to the conclusion that her dog would probably be a bit woozy (and a vet visit was still highly advised!) but would most likely get through.  The toxicity of chocolate is dependent on the type of chocolate (dark chocolate far more toxic than the milk chocolate morsels in the cookie dough), the quantity of chocolate (again, quite small) and the size of the dog (mid-to-large).  Sobering though was the realization that eating a single Lindt dark chocolate bar (which I am fond of) would likely be fatal to my eight pound companion -- her size and the quality of chocolate would both be unfortunate.  Luckily she's never been tempted and I am especially careful now.

I've somewhat deliberately done very little research for this post; it is a bit of an exercise in crowd-sourcing some research.  The same compound which gives some of the pleasure to humans from chocolate, theobromine, can apparently cause a dog's heart to race.  But why?  Is it a difference in the structure of the receptors and their affinity for theobromine?  A difference in tissue distribution of the receptor?  Altered pathway dynamics downstream of the receptor?  Differences in the kinetics of eliminating theobromine?  Differences in absorption by relevant tissues?  A combination of some of these? Or perhaps something I haven't thought of and hadn't listed.

Imagine, for example, that it is a difference in receptor signalling.  Is there a difference in turnover rates of the receptor complex?  Of deactivating a receptor once activated?  Are there different downstream pathways, or at least different levels of signalling in the different pathways?  Or perhaps a different level of release of some downstream hormone?

Members of the onion family (Allium) are another no-no for dogs; I believe they cause limited hemolysis.  Why?  What is different about dog blood cells vs. human blood cells?  What is the active agent in onions which does this?

Yet another are grapes.  I think I know the absolute least on this one.  Kidney failure, but how?

Okay, I cheated and checked the ASPCA site and found one more interesting one: xylitol. I think this extends to all sugar alcohols.  So why?  What is it about dog physiology that is different?  Transporters? Missing enzymes?  Perhaps this is an evolutionary consequence of being carnivores, but how does it all play out on the level of proteins, pathways and cells?

A oft repeated phrase in toxicology is that the dose makes the poison.  That is certainly true for a species, but not necessarily true across species.  Are dogs simply more sensitive to these agents due to the same molecular systems being tuned differently, or are there fundamental physiological differences which make us insensitive but doom our tail wagging friends?

Dogs are used for testing in pharmaceuticals for both scientific and regulatory reasons, though it is certainly not something I would ever want to do.  I would hope that the questions I am posing could be explored with cell-based assays, but particularly with the grapes that might not be a reasonable hope.  Perhaps then it is better left a mystery.
However, understanding such physiology of these toxicities could hold practical knowledge.  Drugs and toxins are often powerful means to tease out what is biologically important and these can ultimately lead to further drug development opportunities.  Many times, natural poisons can be turned into useful pharmaceuticals -- digitalis, atropine Other times, they simply prove to be valuable tools for dissecting biology.

To give a favorite example, MTOR is now known to be a critical regulator of a cell's metabolism, and it and other members of its pathway a target of interest for a wide range of diseases, including cancer, metabolic diseases and immunology.  But we knew essentially nothing about MTOR until someone decided to figure out how the natural product rapamycin functions: MTOR stands for Mammalian Target Of Rapamycin.  TRPV1 is an important target for pain research, though I don't know if interest in it predates identifying it as the capsaicin receptor.  Understanding theobromine toxicity in dogs down to the last atom might inform our understanding of cardiovascular conditions; better understanding grape toxicity might reveal a new weakness in kidneys to avoid.  Similarly with alliums and red blood cells.

Every active chemical agent has some sort of story to tell, but only if we pursue finding it. In veneno veritas.


Anonymous said...

Our vet said the chocolate toxicity was due to the caffeine in dark chocolate. Small body weight, high caffeine can be devastating.

I use this on my bird seed for the exact reason you tried chili powder. This stuff works like magic. No squirrels or raccoons, however, 2-3tbsp/ 5lb of seed does result in fewer birds from visiting. I'm still experimenting with the sweet spot: Cole's Flaming Squirrel Seed Sauce

Cliff Beall said...

Many dogs seem to tolerate chocolate fine, maybe there's a sensitivity gene. I did hear of a dog that got very sick after its owner gave it naproxen.

daniele malleo said...

Not sure if this addresses your question, but according to :

"Theobromine and caffeine competitively inhibit cellular adenosine receptors, resulting in CNS stimulation, diuresis, and tachycardia. Methylxanthines also increase intracellular calcium levels by increasing cellular calcium entry and inhibiting intracellular sequestration of calcium by the sarcoplasmic reticulum of striated muscle. The net effect is increased strength and contractility of skeletal and cardiac muscle. Methylxanthines may also compete for benzodiazepine receptors within the CNS and inhibit phosphodiesterase, resulting in increased cyclic AMP levels. Methylxanthines may also increase circulating levels of epinephrine and norepinephrine."