[OrganicSyn1.0]

First off I'm not very well versed in biochemistry...but I have a biochemistry related question that hopefully some of you will entertain. I was always curious why health professionals say acetaminophen (any analgesics for that matter) interact poorly with alcohol (ethanol)? I tried thinking up reaction mechanism arrows but couldn't come up with them. Anyone know the organic/biochemistry behind this reaction?

[Yggdrasil]

The poor interaction with ethanol is not based on any chemistry that occurs between the two substances, but instead is based on the biology of how the body handles these substances.  Both acetaminophen and ethanol are metabolized by the liver and are essentially toxic to the liver.  Consuming both at the same time can overtax the liver's ability to deal with the substances and cause liver damage.

[JGK]

Back in the "olden days" when I studied toxicology, I seem to recall the primary metabolic pathway for ethanol and acetominophen is by sulfation. If one or both are competing for this metabolic route it becomes saturated and other oxidative pathways come into play. These cause the formation of more toxic intermediates.

[curiouscat]

If I remember correctly the funny / non-intuitive part was that if you were indeed a long term alcoholic it'd have been safer if you didn't stop your alcohol while you had to take an acetominophen or two. You should rather not take acetominophen at all but if you did, stopping alcohol before you did was the most dangerous strategy.

The ironic part was most alcoholics who did take acetominophen did it for, say, a flu or a fever or something. And that flu probably caused them to ease up on the alcohol for a day or two. And then when they took an acetominophen it really was the worst time.

The underlying explanation was fun but I won't go into it since I might mess up the details.

[Babcock_Hall]

The primary disposal route of ethanol is by oxidation to acetaldehyde, then to acetic acid, although apparently at least one isozyme of cytochrome P450 is induced and glutathione is depleted.  According to one link I found, the main disposal route for acetaminophen is by conjugation with glucuronic acid:  http://www.chem.ox.ac.uk/mom/acetaminophen/acetaminophen.html
Here is a link to an article that discusses the induction of an aminotransferase (transaminase) enzyme:  http://www.ncbi.nlm.nih.gov/pubmed/10649673  "In long-term alcohol users, the syndrome of hepatotoxicity from acetaminophen taken in therapeutic or modestly excessive doses is distinctive. It is characterized by striking elevation of transaminase levels and the potential for acute liver failure with high morbidity and mortality rates."

Link that discusses a cytochrome P450 isozyme: 
http://www.unboundmedicine.com/medline/citation/11605310/%5BAcetaminophen_use_by_chronic_alcohol_abusers:_a_therapeutic_dose_may_be_too_much_for_the_liver%5D_
"This combination [changes in transaminase levels, cyt p450 levels, and glutathione levels?] causes the formation of a relatively large amount of the radical N-acetyl-p-benzoquinone imine and a low potential to detoxify this metabolite, so that even small amounts of acetaminophen may cause liver damage."

Another link:  http://www.ncbi.nlm.nih.gov/pubmed/15239079  Here is a portion of the abstract:
"A careful look at ethanol and nutrition, especially fasting demonstrates that therapeutic doses of acetaminophen do not place patients at a greater risk in either of these instances. An overdose of acetaminophen in a chronic alcohol abuser may result in more severe hepatotoxicity than in the nonalcoholic. CYP2E1 [a type of cytochrome p450 enzyme] and glutathione must be evaluated simultaneously rather than in isolation. Glucuronidation capacity in humans is not a factor except in massively overdosed patients."

EDT
I can see how low levels of glutathione would be a problem, inasmuch it traps the NAPQI molecule before the latter does any damage.  I have not yet seen an explanation of what a particular aminotransferase is doing.