This is a rough write up, please bear with me.

NAPQI is the toxic metabolite in acetaminophen-induced hepatotoxicity. NAPQI is only produced when pathways of acetaminophen clearance, including clearance of NAPQI itself, are overwhelmed. CYP2E1 is the enzyme which converts acetaminophen into NAPQI. Normally this isn’t a big deal, but becomes problematic when glucuronysltransferases and sulfotranferases (the other two pathways by which acetaminophen is metabolized) are overwhelmed. To remove NAPQI from the body, cells have to deplete useful anti-oxidizing resources. Once these become depleted, NAPQI begins malevolently binding to all sorts of proteins, resulting in their dysfunction or targeting for removal. NAC, the center of treatment planning for acetaminophen overdose, replenishes these anti-oxidizers, allowing the NAPQI to be cleared.

In the setting of chronic alcohol abuse, the body will begin to upregulate CYP2E1 production as a response to needing more for alcohol metabolism. This makes chronic alcohol use an enhancer of CYP2E1. Because you have more enzyme around as a chronic alcohol abuser, you have more processing of acetaminophen via CYP2E1, producing more NAPQI, and thus resulting in worse hepatotoxicity. This ultimately is why the max dose for acetaminophen (Tylenol) is 4g (recently lowered to 3g) for normal individuals, but 2g for chronic alcoholics.

Alcohol in the IMMEDIATE will inhibit CYP2E1. This means acetaminophen will hang around a little while longer while the other clearance pathways are doing their thing, eventually being able to get around to clearing the acetaminophen. Essentially, as it is also metabolized by CYP2E1, acute alcohol in the setting of acetaminophen overdose will keep CYP2E1 busy, letting the healthy metabolizers outpace it. These effects of acute alcohol use inhibiting but chronic use inducing CYP2E1 were referred to by my pharm prof as the “ethanol-acetaminophen paradox”, and stuck with me.

That said, acute alcohol ingestion has not been shown to have a protective effect against acetaminophen overdose in non-alcohol-abusing individuals. The evidence that it may be protective in alcohol abusers while not strong, has been demonstrated. There’s certainly no reason to think you can immediately drink yourself out of an acetaminophen overdose. The aforementioned treatment, NAC, has some strange interactions with alcohol that may amplify liver damage based on how long after drinking one is provided NAC. So even if acute alcohol ingestion were to meaningfully slow acetaminophen poisoning, it may modify the key treatment to be more harmful, and thus is highly NOT recommended.

P.S. None of this is medical advice, please seek advice from a physician only.

umair-akbar-3 s2.0 B9780124172050000250 f25 22 9780124172050 - Effects of Concurrent Alcohol Consumption and Acetaminophen Toxicity: Mechanism