A very short introduction to toxicology and drug interactions
Author: Rachel Nguyen
Artist: Rahel Kiss
Editor: Nirvan Marathe
On an autumn day in 1996, Karen Wetterhahn, a Dartmouth chemistry professor and toxic heavy metal researcher, was working with dimethylmercury, when she accidentally spilled a few drops on the back of her latex glove. Five months later, she presented at the emergency room with an array of neurological deficits, from ataxia to visual blurriness and hearing difficulty. Further investigations later revealed those few dimethyl mercury drops that she had been so unwary of had penetrated through her latex gloves, diffused through her skin, and travelled to the liver, where it is metabolised into methylmercury. Methylmercury then rapidly infiltrated fat tissues, most importantly the brain and the myelin sheath, which wraps around axonal bodies. This lipophilic molecule induced neuronal loss and gliosis observed across her frontal lobe, cerebellum, and visual and auditory cortices; the radical damage and oxidative stress was so extensive that it sent her into episodes of extreme agitation and ultimately, an irreversible coma.
Although only a very small percentage of the world population might come into contact with dimethyl mercury, the rest of us are constantly exposed to toxins everyday – from the food we consume, the medication we take, and the air we breathe in. In fact, paracetamol poisoning is one of the leading causes of acute liver failure in Western countries, primarily due to its combined use with either alcohol or other prescribed medications. A concept far more familiar among the general public is food poisoning. In 2008, a 20-year-old college student from Belgium was found to be hypoglycemic and in fulminant liver failure after unknowingly consuming pasta that had been left unrefrigerated for 2 days. A post mortem autopsy confirmed traces of Bacillus cereus toxin in his liver and bile, which was responsible for fatty acid buildup and liver necrosis. It is noteworthy that, although this is an extreme case of food poisoning, understanding the pathogenesis of common toxicological responses will save many of us from unnecessary trips to the emergency room and, in the worst case, death.
Factors affecting toxic response
One of the factors affecting the toxic response is its variation between different species. For instance, cats are more vulnerable to paracetamol-induced liver damage because they lack the enzymes responsible for converting paracetamol to a non-toxic, soluble metabolite, (discussed in more detail below). Moreover, different inbred strains of an animal might demonstrate a range of toxic responses. A similar phenomenon is observed in humans, primarily due to genetic polymorphisms that result in less functional metabolic enzymes. Perhaps one of the most well-known examples of such a polymorphism is alcohol flush reaction, where a variation in the aldehyde dehydrogenase gene (encodes for the enzyme responsible for converting acetaldehyde produced by alcohol breakdown), results in little to no aldehyde dehydrogenase. This leads to a buildup of alcohol metabolite, causing increased blood flow via vasodilation.
Genetic polymorphisms in other enzymes can have far more significant consequences. For instance, polymorphisms in cholinesterase genes can reduce the metabolic rate of succinylcholine, a muscle relaxant. As a result, muscle relaxation is prolonged and can quickly accelerate from being therapeutic to being fatal.
Important drug profiles in clinical toxicology
Any medications, after oral ingestion, will be metabolised in the liver via two pathways:
- Phase 1: a functional group is added to be further conjugated in Phase 2. These reactions include: oxidation (catalysed by the enzyme family cytochrome P450) reduction, and hydrolysis.
- Phase 2: a polar functional group is added to make the compound hydrophilic and easier to be excreted by the kidneys
It is important to note that the CYP450 family can be induced by a number of exogenous substances, namely alcohol and anti-epileptic drugs (i.e barbiturates). It is extremely important to remember not to take paracetamol at the same time as taking these substances.
The case of paracetamol:
Paracetamol is one of the most common painkillers given to the general public. 95% of ingested paracetamol is metabolised via conjugation by glucuronidase, forming hydrophilic products that can be excreted in the urine. The remaining percentage of paracetamol undergoes oxidation by CYP450, producing the toxin NAPQI. Fortunately, in a healthy individual, NAPQI is rapidly converted by glutathione into non-toxic, soluble paracetamol conjugates. However, when alcohol consumption occurs in tandem with paracetamol ingestion, the balance shifts towards CYP450, causing a buildup of NAPQI. More potently, as this NAPQI accumulates, the activity of glutathione is also overridden. Unconjugated NAPQI disrupts the hepatocellular membrane and depletes the level of glucuronidase enzyme, resulting in a vicious cycle, which causes hepatocellular injury.
Fortunately, there are alternatives. Ibuprofen, an equally-popular NSAID for headache treatment, is absorbed by the gut into the bloodstream and rapidly excreted into the urine. This process relies only marginally on liver metabolism. Therefore, those looking for a remedy to their hangover headache should consider switching to ibuprofen.
Alcohol is not the only exogenous compound that can induce a lethal reaction. Grapefruit juice, a seemingly harmless food product, was confirmed to prolong the QT interval in both individuals with long QT syndrome and those being treated for it. This can lead to lethal arrhythmias and,in some cases, sudden cardiac arrest. One study found that a plausible culprit could be furocoumarins. When absorbed by the enterocytes, furocoumarins are converted to reactive intermediates that bind to and inactivate CYP3A4, a member of (you guess it) the CYP450 family. This increases the oral bioavailability of cardiovascular medications (e.g. nisoldipine, used to treat hypertension), which means a higher-than-recommended amount of active drug is found in its intended tissues, potentially causing overdose.
What is the key takeaway from this? While science is heading towards a personalised medicine model, where every individual’s genetic profile is filtered for any defects (for example, in the CYP450 enzyme) that might affect their pharmacotherapy, this approach is far from being widely implemented. What you can do instead, when picking your over-the-counter medicine (or in fact any kind of medicine), is to 1) check for their route and (primary) site of metabolism (i.e. paracetamol versus ibuprofen), 2) consult with your GP about any underlying medical condition and whether your diet could potentially interfere with your prescribed medications (you can also take extra precautions and read the neatly folded medical instruction sheet inside the cover of your prescription). Oh, and while you’re at it, toss away those leftovers that have been at the back of your fridge for 3 days.