Apparently coffee and Tylenol don't mix

Just heard via the CBC (the Canadian equivalent of the BBC) web site about a recent study that found that caffeine, the stuff in coffee that perks you up in the morning, apparently promotes the conversion of acetaminophen (paracetamol, Tylenol) into a super toxic liver poison.

Now, as I understand it, acetaminophen is metabolized via several pathways in your liver (the primary site of drug metabolism), most of which end with the addition of a water-soluble group (e.g. sulfate or glucuronide conjugation) that leads to the removal of the drug via kidneys in the urine. However, if these pathways are overwhelmed (e.g. you eat an entire bottle of Tylenol, including or excluding the container), acetaminophen is shunted to another pathway, catalyzed by an enzyme called CYP 2E1, which converts it to a toxic metabolite called N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is a real sonofabitch; It is highly reactive and so is able to bind non-specifically to liver cells and cause significant liver damage, potentially leading to liver failure (and death). A small amount of NAPQI is produced even when you take a normal dose of acetaminophen, but your body is able to handle it without problems.

The authors of the study found that caffeine was able to bind to a related enzyme called CYP 3A4 and act in such a way as to enhance the ability of this enzyme to convert acetaminophen into NAPQI. I have to confess at this point that I'm a wee bit confused by the relevance of this finding, since my understanding is that acetaminophen is not appreciably metabolized by CYP 3A4, even in the event of an overdose.

Furthermore, the investigators used doses of acetaminophen and caffeine that far exceed the levels of typical daily consumption of these drugs by most people, so even if CYP 3A4 does indeed convert acetaminophen into a toxic metabolite and caffeine enhances this process, it is likely only relevant to a small group of people: Those who take too much Tylenol on a regular basis AND consume coffee like a marathon runner consumes water.

In any event, liver damage is an insidious thing, since you can damage a large part of the organ before any symptoms of the destruction show up. It's possible that people who drink a tonne of coffee and pop Tylenol on a regular basis are doing damage to their liver, and that this damage is accumulating over time, leading to possible problems down the road. Now for a little public service bit. Alcohol (ethanol) definitely enhances the ability of CYP 2E1 to convert acetaminophen into NAPQI, so doing shots of tequila while popping Tylenol for a headache is a terrible idea. Respect your liver, people.

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