On designer chemical weapons

I’ve been traveling a fair amount recently, and probably have alot to catch up on here. One of the more interesting meetings I went to was the Gordon Conference on Chemical and Biological Terrorism Defense, in Ventura, CA. In the Gordon Research Seminar for students that preceded the conference I was fortunate to hear one of Clem Furlong’s students, Judith Marsillach-Lopez, speak on “Isolation and characterization of human biomarkers following exposure to organophosphates.” While the talk was great, the background on the compound tri-ortho-cresyl phosphate (TOCP) was really quite interesting. As one of Clem’s (and Oksana Lockridge’s) manuscripts nicely summarizes (Schopfer et al. (2010) Anal Biochem 404:64), this compound was originally associated with so-called ‘ginger jake paralysis,’ which came on because of the presence of this compound in Jamaica ginger, a patent medicine for stomach upsets (and source of alcohol during Prohibition). More recently, though, this compound has made a number of other appearances, most interestingly in association with so-called ‘aerotoxic syndrome.’ Airplanes are one of the last places you can encounter TOCP, since most other commercial uses have been discontinued. Unfortunately, within the complex ecosystem that is an airplane its use as an engine lubricant and in hydraulic fluids sometimes leads to contamination of the recirculated air supply. Passengers have reported ‘dirty sock smells,’ and that exposure has in turn sometimes led to, well, this:

Yes, that’s right, TOCP is essentially a nerve agent. Its mechanism of action is quite fascinating. To borrow again from Clem’s most excellent paper:

I suspect that as usual that’s completely distracting, but I shall eventually figure out Teh Intertubes and thus how to insert pictures and whatnot. Anyway, the basic mechanism first involves hydroxylation of one of the aromatic methyls by ‘liver microsomes,’ followed by activation via cyclic phosphate formation (not unlike what we see for RNA self-cleavage; CH339L students take note!), followed by attack by a serine nucleophile on that cyclic phosphate and covalent attachment of the compound to the protein containing the serum. Unfortunately, such very active serine nucleophiles are commonly found on proteins like … acetyl cholinesterase, one of the primary enzymes that regulates the transmission of chemical signals in our nervous system. Once you modify the enzyme acetyl cholinesterase, you can’t break down the neurotransmitter acetyl choline, and your nerves are more or less stuck in the ‘on’ position.

Acetyl cholinesterase is a common target of nerve agents, which often are phosphate or phosphonate derivatives, and add themselves to this critical enzyme. The science and art of making nerve agents has for the most part involved making phosphates or phosphonates that are reactive, and that have low vapor pressures (and thus get into your body via inhalation quite quickly). More advanced engineered qualities include persistence in the environment and perhaps the ability to stick to virtually everything. Nerve agents are often possessed of a beautiful chemical simplicity, and a diabolical biological outcome. While I often rant on about biological threats, it is really chemical threats that scare the holy hell out of me. They’re far easier to make in many cases, and, like nuclear weapons, we seem to have somehow lost our innocence in terms of their use. Thanks Fritz Haber.

TOPC is not high on the list of things that are really scary. There are many scarier compounds, although mostly not in our immediate environment. What really struck me about TOPC was its mechanism of action. ‘Liver microsomes’ is one of those biochemistry codes that means “transformation by cytochrome P450.” Cytochrome P450 enzymes are usually the good guys in our liver, taking hydrophobic compounds (like TOPC) and adding hydrophilic groups (like hydroxyls) to them, allowing their solubilization and eventual elimination from the body. It is in large measure the wondrous suite of cytochrome P450s (there’s, like, 57 of them!) that have kept us from succumbing to the inventive toxic brews of bacteria, fungi, plants, and insects. Unsurprisingly, since different branches of humanity have encountered different bad things, there are many different cytochrome P450 enzymes. Also unsurprisingly, this makes a bit of a difference in how we handle our own semi-toxic brews (i.e., pharmaceuticals):

“Polymorphisms in the CYP [cytochrome P450] family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers.” (from Zhou et al. (2009) Drug Metab Rev 41:89)

We’re entering the age of personalized medicine, where allelic differences between individuals will lead to differences in the way we perform medicine. There are already drugs that initially seemed to have failed in the clinic, only to be revitalized by findings that they work on particular sub-populations with particular enzyme variants. But even though this is true, it wasn’t until I was in the Gordon Research Seminar that I realized that the same principles that apply to modern medicine might apply to modern chemical warfare. Again from Schopfer et al.:

“… some individuals are significantly more sensitive than others to cabin air oil exposure. We hypothesize that this is most likely due to the well-known individual difference in OP (organophosphate) metabolism by cytochrome P450. Cytochrome P450 catalyzes the first step in the converstion of TOCP ….”

And there you have it: clever chemists of today, armed with the vast armada of information about the distribution and specificities of P450 variants, can now countenance making designer chemical weapons that will work on particular genetic populations. The distribution of P450 variants is such that ethnospecificity is thankfully not within reach, but there are certainly genetic skews that might make your enemy of choice a particularly appealing target for some compounds, while conversely not affecting your own people. This is one of many reasons that I am very happy to be living in a melting pot, protected by a military that is also largely a melting pot.


- originally posted on Thursday, April 14th, 2011