The recent poisoning of North Korean dictator Kim Jong-Un’s brother in Malaysia has brought a deadly chemical weapon back into the spotlight.
The death of Kim Jong-Nam, the brother of North Korean dictator Kim Jong-Un, took 20 minutes and was likely to have been very painful. Results from his autopsy confirmed the suspicion that he was poisoned with the lethal neurotoxin, VX.
VX is an organophosphorus compound that was banned in the chemical weapons treaty signed in Paris in 1993. You may have encountered this family of chemicals from their use as insecticides – I know I did.
Malathion, a member of this family, was used in the South for Boll Weavil eradication in the 1960s and 70s. I happened to have grown up in south Alabama in a house that sat beside a large cotton field. During cotton growing season I would climb a huge magnolia tree in my back yard, and from its highest branches I watched crop dusters looping through the air and spraying the cotton fields, oblivious to the fact that in doing so I was most certainly exposed to the vapor. Fortunately, malathion was sprayed in a very diluted form and is less potent than its chemical cousins (It must be true – I’m still here).
VX, like sarin, mustard gas, and similar toxins, acts on synapses that use the neurotransmitter acetylcholine (Figure 1.). At these so-called “cholinergic” synapses, acetylcholine is released from presynaptic terminals and diffuses across the gap between synapses to bind to receptors. These receptors can be either on brain cells or muscles. When it binds, acetylcholine generally causes excitatory responses. This can result in normal muscle contractions or excitatory neural responses.
The action of a neurotransmitter must be terminated or there can be big trouble. For almost all neurotransmitters, proteins transport or take up the transmitter into the synaptic terminal from which it is released. The transmitter may also be deactivated by proteins that break down the neurotransmitter molecule. In the case of acetylcholine, this is accomplished by the enzyme acetylcholinesterase.
Acetylcholinesterase dwells in the cholinergic synapse in the membrane near the receptors, and directly terminates the action of the neurotransmitter acetylcholine by degrading the molecule into choline, which is then transported back into the transmitting terminal so that new acetylcholine can be made and released. A single cholinesterase can break down about 25,000 transmitter molecules, so disrupting it can cause significant accumulation of the transmitter in the synapse.
VX and related nerve toxins inhibit the acetylcholinesterase, leading to accumulation of the transmitter in the synapse. This leads to massive activation that persists because the toxin’s hold on the esterase is practically irreversible. Muscles contract, and central and peripheral nerves essentially seize up with the activity, including the heart and diaphragm muscles.
What happens next? Well, “VX” is short for “Venomous agent X”. Is death inevitable? Probably.
Antidotes to VX are indirect, and rely on low-level exposure to the toxin. Atropine, a common chemical warfare antidote, doesn’t directly counteract the effects of cholinesterase inhibitors, but by blocking receptors that would normally bind the excess acetylcholine. The effects of the toxin might be somewhat minimized in this way. However, VX is particularly nasty stuff. Troops carry autoinjectors with the idea that use of atropine will counteract organophosphate-based chemical weapons, but unless atropine is administered immediately it may lessen, but not eliminate, the effects of the toxin. Chemical agents called oximes are proposed to refresh the bound cholinesterases, but running human trials of this would obviously be challenging – and the few studies do not support significant protection.
When it comes to these dangerous chemicals, the best defense is to stay away from them. Unfortunately for Kim Jong-Nam, as Harper Lee wrote in To Kill a Mockingbird, “You can choose your friends but you sho’ can’t choose your family”.
References where you can find out more:
Goldstein A. (1944). The mechanism of enzyme-inibitor-substrate reactions illustrated by the cholinesterase-physostigmine-acetylcholine system. J Gen Physiol. Jul 20;27(6):529-80.
Army video on chemical weapons and effects (warning – rather gruesome): https://www.youtube.com/watch?v=eW7SOyuoO0o
Background Chemistry for Chemical Warfare Agents and Decontamination Processes in Support of Delisting Waste Streams at the US. Army ‘Dugway Proving Ground, Utah. https://www.osti.gov/scitech/servlets/purl/258187/
USDA Q&A on Bool Weevil Eradication: https://www.aphis.usda.gov/publications/plant_health/2013/faq_boll_weevil_erad.pdf
Crop duster spraying cotton fields a few miles from where I grew up. https://www.youtube.com/watch?v=Ymqr-e699nY
Buckley NA, Eddleston M, Li Y, Bevan M, Robertson J. (2011) Oximes for acute organophosphate pesticide poisoning. Cochrane Database of Systematic Reviews 2011, Issue 2. Art. No.: CD005085. DOI: 10.1002/14651858.CD005085.pub2
Eddleston M, Szinicz L, Eyer P and Buckley N (2002) Oximes in Acute Organophosphate Pesticide Poisoning: a Systematic Review of Clinical Trials. QJM 95(5): 275–283.