Clinical scenario Acetaminophen overdose

[lifelong]

Ok, I have one for you guys,

I am in clinical doing my thing...and I get an acetaminopen overdose through the ER. I have spent the last few days researching this...trying to learn/understand and still can't get a handle on the metabolism of this...

From what I gather 90% of this drug gets immediately metabolized through the liver and excreted. It's the remaining 10% I am struggling with. Again from what I read...10% of acetaminophen goes through CYP2E1 creates a toxic reactive N-acetylimidoquine (NAPQI) substance which then binds to liver cells producing hepatic cell lysis. Glutathione initially binds with this and converts this to a nontoxic substance, right? Then if the Glutathione is depleted (ETOH, malnutrition, etc.), not enough is available (overdose) or competition (drugs) for the enzyme sites then toxicity occurs. Isn't Glutathione involved in the other 90%, how can it be specific?

I get all the other stuff, antidotes...etc... it's the metabolism that has me baffled and I would to understand this at a cellular level. Anyone want to try?

Thanks!

[MagsMom]

if anyone understands this pathway differently - please feel free to correct my explanation. i really like biochemistry and i am reaching back to my biochem class so make sure you double check my memory! also - i will apologize in advance if this reads in an elementary way but i don't know how else to phrase it.

first - as you mentioned, normally, 90% of acetaminophen is immediately metabolized. about 75% goes through the glucuronidation pathway and 15% goes through sulfation pathway. so through glucuronidation the acetaminophen has a glucuronic acid added which makes the acetaminophen more water soluble and therefore suitable to be eliminated by the kidneys in urine. the same thing basically happens with sulfation - a sulfate group is added rendering the acetaminophen more suitable to be eliminated by the kidneys. so, getting to that 10%.... the rest of the acetaminophen is metabolized by cytochrome p450 pathway (you mentioned the p450 subfamily cyp2e1 - i actually don't know the metabolic pathway to that detail since there are several subfamilies in p450 - so i am only able to generalize).

ok - then, yes, the cytochrome p450 pathway will take the acetaminophen and create an intermediate napqi which then has the reaction with glutathione. when there is too much acetaminophen then the first two pathways (which do the 90%) get saturated so more acetaminophen is shuttled to the p450 pathway and ultimately needing to react with glutathione to be detoxified. for reasons you mentioned (alcoholics, malnutrition, drug interactions, etc) there may either not be enough glutathione stored or it can simply run out. glutathione eventually gets depleted leaving liver cells susceptible to oxidative damage by the reactive intermediate napqi causing necrosis of the hepatocytes - there is a more specific answer to exactly how the intermediate binds to cause damage but i will have to look that up if you want to know.

to answer your question "isn't glutathione involved in the other 90%, how can it be specific?" no - it is not involved in the 90% because glutathione is not found in those pathways and it is that specific. glutathione is involved in normal metabolism of acetaminophen, however, only when it is shuttled through the p450 system.

let me know if that answers your question - if not i can go to my biochem notes and look up a more detailed explanation.

[lifelong]

Thank you MagsMom,

I am taking in as much as I can...and really needed help understaning this concept better. Thank you. I learn so much from this forum and hope to add light and help others as able.

Tracey

[celclt]

awesome job magsmom!