With Memorial Day approaching and summer just around the corner, it’s time to prepare for the usual seasonal annoyances: mosquitoes, ticks, and visiting relatives (worse — bug spray doesn’t work on them). But perhaps the most insidious summer surprise is the ever-hideous poison ivy [1].
Poison ivy is some nasty-ass stuff. But if you read this nasty-ass article to the end, at least you’ll no longer need to scratch your head about why you’re scratching the rest of you. You’ll understand precisely why you’re miserable. It’s all about chemistry, metabolism, and toxicity.
Experienced medicinal chemists [2] often develop a superpower known as “eyeball toxicity”—the uncanny ability to glance at a molecule’s structure and predict whether it’s likely to be toxic. This trick, however, only works in one direction. It’s relatively straightforward to look at a group of molecules and pick out the toxic ones [3], but it’s nearly impossible to go the other way: predict which ones are safe by looking at the chemical structure.
That’s because chemists have learned to recognize toxicophores—specific chemical fragments or substructures that tend to cause trouble. These molecular red flags show up across a wide range of unrelated compounds. They’re frequently associated with mutagenicity, carcinogenicity, or organ damage. Think of them as nature’s little biochemical landmines.
Figure 1. Common toxicophores include nitroaromatics, aminoaromatics (anilines), quinones, and alkyl halides. Chemicals bearing them are generally bad news.
Now, let’s look at three naturally occurring molecules (Figure 2) and see if any obvious themes emerge.
Figure 2. Molecule A contains a long chain of carbon atoms, one carbon-carbon double bond, and two hydroxyl groups. Molecule B contains one carbon-carbon double bond, two phenyl rings, and three hydroxyl groups. Molecule C also has a long chain of carbon atoms, five carbon-carbon double bonds, and one hydroxyl group. How "good" are these chemicals?
The answer is "who knows?" All three molecules have common structural elements. But there is no obvious toxicophores. So unless you happen to know something about these structures, there’s no way to tell which of these will be good, bad or neither. But we know plenty about all of them.
The real answer: one bad, one good, and one neither. Molecule A is bad. It is called urushiol [4]. It is the chemical in poison ivy that is responsible for doing all kinds of hideous things to you. Molecule C is good. It is vitamin A, without which you will go blind [5]. Molecule B is useless. It is called resveratrol. Although it was touted as an antioxidant therapy to fight heart disease, inflammation, and aging, a resveratrol formulation called SRT501 did none of these, something that cost GlaxoSmithKline $720 million to find out in failed clinical trials.
Both urushiol and Tylenol are inherently non-toxic. And then they're not.
So how does a harmless-looking molecule like urushiol unleash dermal hell? It turns out that urushiol has just the right features to pull this off. Its oily nature makes it easily absorbed into the skin (and also nearly impossible to wash off). Then, your liver enzymes gladly pitch in and do the rest.
At this point, chemistry plays its part (Figure 3). Coincidently, these same properties are also why Tylenol can be toxic. Both molecules are harmless until oxidative metabolism by CYP enzymes occurs, producing two chemically reactive groups—a quinone (L) and a quinone imine (R). Chemically reactive drugs, which often contain one or more of the toxicophores shown in Figure 1, are usually verboten; they find proteins and DNA fragments and alkylate them. Not good. DNA alkylation is a hallmark of mutagenicity.
Figure 3. Neither urushiol nor Tylenol (acetaminophen) are toxic until they are oxidized. The reactive part of both molecules is shaded in blue.
So, I wish you an itch-free (and relative-free) summer. But if you're not careful (three leaves and shiny) a toxic natural chemical, one of thousands of such chemicals out there will make your life miserable.
Much like this article possibly did. If reading it gave you a headache you could try some Tylenol, or a placebo, if you prefer. They’re about equally effective, give or take the placebo effect. Getting rid of your relatives? Not so easy.
NOTES:
[1] Poison ivy, sumac, and oak all synthesize the same toxin, urushiol.
[2] Medicinal chemists are trained as synthetic organic chemists, meaning they’re capable of transforming one molecule into another in the most efficient way by choosing the right reaction(s). Once organic chemists enter pharmaceutical research, synthesis becomes merely a tool to make molecules with specific properties and biological activities. Medicinal chemistry is the essence of drug discovery.
[3] No one will get it right all the time. Different chemists have used or read about an enormous variety of different chemicals in their careers. So, Chemist A may recognize a toxicophore that Chemist B is not familiar with.
[4] Urushiol is actually a mixture of several similar chemicals with similar properties. Why have I selected this one? The urushiol variant shown is one of the most toxic: it has a 15-carbon side chain with three double bonds. This analog is highly unsaturated, making it more susceptible to oxidation and thus more reactive with skin proteins—an important feature in triggering the immune response. It's also structurally representative of the class and ideal for illustrating the toxicophore mechanism.
[5] Vitamin A is not a panacea. Doses as little as 2-3X that of the RDA can be toxic. This is a dangerously narrow therapeutic index.
Josh Bloom
Director of Chemical and Pharmaceutical Science
Dr. Josh Bloom, the Director of Chemical and Pharmaceutical Science, comes from the world of drug discovery, where he did research for more than 20 years. He holds a Ph.D. in chemistry.
