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Pharmacology Sciences

[Sciences/Pharmacology] A tale of death by licorice poisoning

I guess you have heard in the last couple of days about this poor man death from a severe cardiac condition triggered by a severe case of hypokalemia (low potassium levels) as reported by the APNews here. The culprit in this death? Overconsumption of black licorice (one pack a day for few weeks).

So, how can it be possible? Well, to understand how licorice can be dangerous, and how this case is another validation of Paracelsus axiom “the dose makes the substance poison”, we have to go back into some biology and chemistry, all wrapped up in what we call “Pharmacology” and especially a sub-genre of it we call “Toxicology”.

Licorice (Glycyrrhiza galabra, remember that name for later) is an herb commonly found in Europe and West Asia, with edible roots. It can be consumed as-is by chewing and sucking the dry roots (I used to buy them from my pharmacist as a treat) or primarily used for extracting licorice, a black and bittersweet substance.

Like any plants, Glycyrrhiza produce various phytochemicals including chemicals falling into what we call “secondary metabolism”. One of them, glycyrrhizin, is the major chemical sought from these plant, it gives this bittersweet taste that some enjoy and some get repelled (Gosh, I hate processed licorice candies and I would throw my Haribo mixed bags once I ate everything but the licorice ones). Now comes the fun: Here is the structure of licorice:

If you are a chemistry nerd, you will note the two glucuronic acid on the left, but you will find more interest into the polycyclic saturated chain that looks a lot like cholesterol (see below)….

…..or similar to digoxin (a cardiac glycoside that is a potent poison extracted from foxgloves, but also a potent cardiotonic we give to patient suffering from heart failure).

But what is even more interesting is that glycyrrhizin share a lot of structural similarities with steroid hormones including aldosterone (mineralocorticoids, left) and cortisol (glucocorticoids, right):

Glycyrrhizin (or glycyrrhizic acid) is poorly present in the blood and urine, usually found at less than 2% of the injected dose. In the other hand, glycyrrhetic acid (GA), the degradation byproduct is considered the major form that is absorbed and distribute into the body. GA is mostly eliminated via liver metabolism (GA-3-glucuronide) but interestingly can get salvaged by the gut microbiota back into GA and re-enter the body as GA, hence resulting in a pretty long elimination half-life (between 6-10 hours, which would mean it would take 1 to 2 days to clear out a single dose of licorice).

You can appreciate that we are getting closer when it comes to chemical structure to aldosterone and cortisol. Here comes the interesting part. Cortisol can bind to its cognate receptor (glucocorticoid receptor), but also bind to other steroid receptors like the mineralocorticoid receptors (MR). MR target genes are various, but several of them are encoding for sodium (Na+) channels which will work on kidney epithelial cells to induce reabsorption of sodium in the nephrons. This is turn will change the dynamics of electrolytes, as the reabsorption of sodium (Na+) will result in an increased elimination of potassium (K+) by renal excretion. In turn, we will end up in a hypernatremia/hypokalemia situation which will manifest in any excitable cells, in particular in the heart tissue. Both Na+ and K+ play an important role in the heart electrical activity. Mess around with the extracellular concentration of one of these two and you are setting yourself into serious cardiac issues (arrhythmia, fibrillation, conduction block, impaired or asynchronic muscle contractions….weird EKG patterns ahead).

It would be tempting to assume GA would compete with cortisol, or mimic it for binding to the MR. Turns out, GA does not really fit to MR, but fits quite well into the catalytic site of an enzyme called 11-beta-hydroxysteroid dehydrogenase (11-bHSD). This enzyme will convert the hydroxyl group present in the carbon 11 position (see that OH group pointing on the left in the cortisol and aldosterone molecule?) into a keto group (=O). This is enough to kill the ability of cortisol (which now became cortisone) MR activity. What basically happens is that GA will compete with cortisol for 11-bHSD binding, has better affinity for the enzyme and block the transformation of cortisol into cortisone. Result? You create a buildup of cortisol, which means you have an increased activation of MR, increased expression of its target genes, increased Na+ channels and transporters in the kidneys that will increase its resorption during the renal filtration process…..and the resulting hypernatremia and hypokalemia.

It is very unlikely you will an issue in an acute exposure (the FDA recommends to people over 40 to not eat licorice for more than two weeks, keep it below 2 ounces) but likely to occur if ingested chronically. Plus having an history of cardiac events makes you worse.

So please remember the axiom of Paracelsus: “The dose makes the poison”. Limit your licorice as a once-in-a-week treat, limit your intake and avoid it if you have heart issues.

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