Urushiol

Previously, we have examined the most poisonous of plant toxins, ricin and abrin. They catalyse the destruction of cells by stopping them from making proteins. Today, we are going to explore another group of plant toxins which also targets cellular proteins. Instead of catalysis, these toxins make our body turn on itself! 

 

Anacardium occidentale

Behold the poison ivy, poison sumac and poison oak, all the superstar poisonous plants in the West. They all contain the same class of toxins called urushiol and yet, their close relative the cashew tree is valued as a food crop. In fact, it is the cashew that gave this entire toxic family its name Anacardiaceae. Anacardium is the Greek for 'heart'; occidentale means Occident or America, the plant's origin. If you look carefully at the cashew's fruit (part where the cashew nut is attached), it’s is not technically a fruit, but a pseudofruit that is formed from the pedicel of the flower (true fruit forms from the ovary). The cashew fruit resembles an upside down heart.

 

All parts of the cashew tree contain the toxin urushiol (and related compounds like anacardic acids, cardanol etc), which are especially concentrated in the shell of the cashew nut. What we get commercially have been processed to remove the toxic shell, and roasted to reduce the urushiol content. Even so, there are people who are sensitive to processed cashew nuts, which can lead to fatal allergic reactions. The toxin urushiol is so named after the Japanese lacquer tree, Urushi (Toxicodendrum vernicifluum), from which this group of chemicals were first described. Again, there are many structurally related toxins from the cashew family, we collectively call them urushiol. 

 

Figure 1: Chemical structure of urushiols.

Chemically speaking, urushiol is an oil because all urushiol-type toxins must contain a hydrocarbon chain that is at least 17 carbons long (Figure 1). Hence these molecules are very hydrophobic, non-volatile and insoluble in water. That's also the reason that urushiol can persist on a surface or dead plants, and it be 'smeared around' to many people's suffering. There's even a report where someone inhaled the smoke of burnt poison ivy (containing particles coated with urushiol oil) and died of acute respiratory distress! Similarly dire consequences can be assumed for those who are unfortunate enough to ingest urushiol. That said, urushiol is an interesting plant poison because it is not technically toxic on its own, and it's not toxic to all people. Only some (about 70% of a population) and those who are repeatedly exposed to urushiol become more and more sensitive to its toxic effects. And as aforementioned, urushiol doesn't kill our cells directly, it causes the human immune system to go crazy and turn on itself. There are two ways in which urushiol can do this, the most prevalent is called type IV (four) hypersensitivity reaction, where the body's immune cells recognise the urushiol molecule, remember it as a threat and in a subsequent exposure, launch a kamikaze attack on the urushiol exposed areas, which leads to contact dermatitis. Now bear in mind that a prerequisite first exposure is required, we call that a sensitising event, and that will not result in any symptoms what so ever. It is the subsequent exposures that end up worse and worse. What's more remarkable, one can develop cross-hypersensitivity, where a patient who has not been exposed to say, poison ivy can get severe type IV hypersensitivity because of previous exposure to cashew or mango or vice versa, scary huh! In a second (less documented) scenario of urushiol hypersensitivity (type I), it is the antibodies instead of immune cells that trigger an allergic reaction. In this case, the body releases a lot of itchy, pro-inflammation, vessels dilating signals such as histamine, and in severe cases can lead to anaphylaxis.

Figure 2: Urushiol toxicity, mechanism of action.

How exactly does urushiol induce our immune cells to go crazy? To understand that, we will need to look at the other end of the urushiol's chemical structure. Examine Figure 2 carefully, note the six carbon ring with two oxygen atoms? That's what we call a catechol polyphenol. It is this catechol structure that confers urushiol chemical stability. However, when absorbed into the human skin, the catechol fragment gets oxidised by native enzymes, which remove two hydrogen atoms from the two –OH (phenol) groups. The six carbon ring then rearranges itself, and instead of a catechol, we now have an ortho-benzoquinione, which is highly electrophilic. In other words, the ortho-benzoquinone ring would love to take up electrons and make a new bond (with nucleophiles) to revert into a more stable catechol. Lo and behold, we have negatively charged proteins in the skin called cysteine, which is more than happy to further its cause. Hence, native cysteine containing protein undergoes a nucleophilic addition (molecular hand-shake) with the urushiol in its ortho-benzoquinone form, producing a permanent covalent bond. Satisfied, the ortho-benzoquinone rearranges itself by losing one of its hydrogen atom to regenerate a catechol skeleton. That's it! In otherwise non-urushiol sensitive individuals, who cares? But to sensitive individuals, the immune system doesn't like this protein-urushiol complex, so arrrests it and takes it to the police station to be filed as criminal. The chief officer called a T-cell isn't happy about that either, and puts a kamikaze head hunt on any future urushiol-protein complexes. Immunologists call this initially sensitising small molecules (like urushiol) that combine with proteins to form an allergenic substance, haptens. Different immune cells are recruited and sent to the skin on stand by, any future invasion of urushiol (haptens) will spell doom. Such is the biochemical basis of urushiol induced type IV hypersensitive reaction.

You may wonder, is that the fault of a plant metabolite? Or perhaps more intriguingly, it's the fault of our human body's evolutionary history? Evolution dictates that we are a bunch of trade-offs. The human immune system is one of the most complicated in the animal kingdom, it protects us against a hoard of harmful substances, but it needs training and modesty. When the human immune system acts inappropriately, as in the scary arms race of plant toxins vs humans, what supposedly protects us turned out as the greatest enemy.