Poison Ivy and Tylenol
Derek Lowe
suffers from a bit of Poison Ivy and talks about the similarity between it an Tylenol and muses on whether Tylenol (or even Aspirin) would make it to the market as a new drug these days:
Remind Me Not to Do This Again
As I sit here typing this evening, my right arm is giving me fits. About a week ago, I had the misfortune, while retrieving a mis-thrown frisbee in the back yard with my two children, of reaching into an area with some poison ivy growing in it. And I’ve been paying for it ever since.
My immune system has been set off by contact with an alkylated catechol called urushiol (lot of information here.) The stuff penetrates the skin quite well, damn it all. It’s simultaneously greasy (with a fifteen-carbon tail on it) and has a polar head group (the catechol), so it just wanders in there will all the other lipid molecules and does its thing. Its thing is to get oxidized to an ortho-quinone, which is probably what does the damage.
Quinones are reactive beasts, which is why we don’t put catechol groups (or similar precursors) on drug structures if there’s any possible way around it. Some years ago, Merck made a big splash in Science and other venues with a small molecule that affected the signaling of the insulin receptor. That was quite a feat, and worthy of the attention - but the molecule itself, derived from a natural product, was a quinone. I rolled my eyes when I first saw it, as did almost everyone else in the industry, and we were correct - Merck was never able to develop the stuff into a real drug.
A notorious exception to this rule is acetominophen, known also by its brand-name form of Tylenol, which gets metabolized to a reactive quinone-like compound. (There’s no way that the compound would be seriously developed today, but that almost certainly goes for aspirin, too, and there you have one reason that it’s so hard to run a drug company these days.) The acetominophen metabolite is cleared handily by one of the body’s standard systems (glutathione conjugation), but if you take enough of the stuff to deplete your reserves you’re in for some serious liver damage.
So, this quinone has soaked right into me and reacted with some of my cell-surface proteins, prompting my immune system to mount a big inflammatory attack. This response isn’t just available in your back yard, though: it’s a little-known occupational hazard in research labs. There are many classes of reactive compounds that can penetrate the skin enough to cause trouble. If a particular person’s immune system finds fault with the result, they end up with dermatitis that’s indistinguishable from vigorous, prolonged poison ivy contact.
Derek's commentors post some of their own experiences. The human body is a fascinating (and somewhat exasperating) system...
Posted by DaveH at September 12, 2005 9:50 PM