NAPQI

File:Acetaminophen metabolism.png

In adults, the primary metabolic pathway for paracetamol is glucuronidation. This yields a relatively non-toxic metabolite, which is excreted into bile and passed out of the body. A small amount of the drug is metabolized via the cytochrome P-450 pathway (to be specific, CYP3A4 and CYP2E1) into NAPQI, which is extremely toxic to liver tissue, as well as being a strong biochemical oxidizer. In an average adult, only a small amount (approximately 10% of a therapeutic paracetamol dose) of NAPQI is produced, which is inactivated by conjugation with glutathione (GSH). The amount of NAPQI produced differs in certain populations.{{Citation needed|date=April 2009}}

The minimum dosage at which paracetamol causes toxicity usually is 7.5 to 10g in the average person.{{Cite web|url=http://emedicine.medscape.com/article/820200-overview|title = Acetaminophen Toxicity: Practice Essentials, Background, Pathophysiology|date = 5 October 2021}} The lethal dose is usually between 10 g and 15 g.{{Citation needed|date=February 2013}} Concurrent alcohol intake lowers these thresholds significantly. Chronic alcoholics may be more susceptible to adverse effects due to reduced glutathione levels.{{Cite web |title=NIH Publications |url=http://pubs.niaaa.nih.gov/publications/arh23-1/40-54.pdf |website=pubs.niaaa.nih.gov}} Other populations may experience effects at lower or higher dosages depending on differences in P-450 enzyme activity and other factors which affect the amount of NAPQI produced. In general, however, the primary concern is accidental or intentional paracetamol overdose.

When a toxic dose of paracetamol is ingested, the normal glucuronide pathway is saturated and large amounts of NAPQI are produced. Liver reserves of glutathione are depleted by conjugation with this excess NAPQI. The mechanism by which toxicity results is complex, but is believed to involve reaction between unconjugated NAPQI and critical proteins as well as increased susceptibility to oxidative stress caused by the depletion of glutathione.{{cite book| pmc=2836803 | pmid=20020268 | doi=10.1007/978-3-642-00663-0_12 | issue= | chapter=Mechanisms of acetaminophen-induced liver necrosis | year=2010 | pages=369–405 | vauthors=Hinson JA, Roberts DW, James LP| title=Adverse Drug Reactions | series=Handbook of Experimental Pharmacology | volume=196 | isbn=978-3-642-00662-3 }}

The prognosis is good for paracetamol overdoses if treatment is initiated up to 8 hours after the drug has been taken. Most hospitals stock the antidote (acetylcysteine), which replenishes the liver's supply of glutathione, allowing the NAPQI to be metabolized safely. Without early administration of the antidote, fulminant liver failure follows, often in combination with kidney failure, and death generally occurs within several days.

NAPQI becomes toxic when GSH is depleted by an overdose of acetaminophen, Glutathione is an essential antidote to overdose. Glutathione conjugates to NAPQI and helps to detoxify it. In this capacity, it protects cellular protein thiol groups, which would otherwise become covalently modified; when all GSH has been spent, NAPQI begins to bind to certain enzymes like N-10 formyltetrahydrofolate dehydrogenase and glutamate dehydrogenase, reducing their activity and killing the cells in the process. This, along with the depletion of GSH which significantly impairs the function of mitochondria, plays a significant role in the development of paracetamol toxicity.{{cite journal | vauthors = Hinson JA, Roberts DW, James LP | title = Mechanisms of acetaminophen-induced liver necrosis | journal = Handbook of Experimental Pharmacology | issue = 196 | pages = 369–405 | date = 2010 | pmid = 20020268 | pmc = 2836803 | doi = 10.1007/978-3-642-00663-0_12 }}

The preferred treatment for an overdose of this painkiller is the administration of N-acetyl-L-cysteine (either via oral or IV administration){{cite web|url=http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20%28General%20Monographs-%20M%29/MUCOMYST.html |title=Pharmaceutical Information – MUCOMYST |publisher=RxMed |accessdate=2014-02-13}}), which is processed by cells to L-cysteine and used in the de novo synthesis of GSH.

• Cytochrome P450 oxidase
• Liver failure
• Centrilobular necrosis

{{Reflist}}

• {{cite journal |vauthors=Alsalim W, Fadel M |title=Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Oral methionine compared with intravenous N-acetyl cysteine for paracetamol overdose |journal=Emerg Med J |volume=20 |issue=4 |pages=366–7 |date=July 2003 |pmid=12835357 |pmc=1726135 |url=|doi=10.1136/emj.20.4.366}}
• {{cite journal |vauthors=van de Straat R, de Vries J, Debets AJ, Vermeulen NP |title=The mechanism of prevention of paracetamol-induced hepatotoxicity by 3,5-dialkyl substitution. The roles of glutathione depletion and oxidative stress |journal=Biochem. Pharmacol. |volume=36 |issue=13 |pages=2065–70 |date=July 1987 |pmid=3606627 |doi=10.1016/0006-2952(87)90132-8}}

Category:Human drug metabolites

Category:Chemical pathology

Category:Hepatotoxins

Category:Imines

Category:Toxins