Mechanism of Action of N-Acetylcysteine in the Protection Against the Hepatotoxicity of Acetaminophen in Rats In Vivo
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N-Acetylcysteine is the drug of choice for the treatment of an acetaminophen overdose. It is thought to provide cysteine for glutathione synthesis and possibly to form an adduct directly with the toxic metabolite of acetaminophen, N-acetyl-p-benzoquinoneimine. However, these hypothese have not been tested in vivo, and other mechanisms of action such as reduction of the quinoneimine might be responsible for the clinical efficacy of N-acetylcysteine. After the administration to rats of acetaminophen (1 g/kg) intraduodenally (i.d.) and of [(35)S]-N-acetylcysteine (1.2 g/kg i.d.), the specific activity of the N-acetylcysteine adduct of acetaminophen (mercapturic acid) isolated from urine and assayed by high pressure liquid chromatography averaged 76+/-6% of the specific activity of the glutathione-acetaminophen adduct excreted in bile, indicating that virtually all N-acetylcysteine-acetaminophen originated from the metabolism of the glutathione-acetaminophen adduct rather than from a direct reaction with the toxic metabolite. N-Acetylcysteine promptly reversed the acetaminophen-induced depletion of glutathione by increasing glutathione synthesis from 0.54 to 2.69 mumol/g per h. Exogenous N-acetylcysteine did not increase the formation of the N-acetylcysteine and glutathione adducts of acetaminophen in fed rats. However, when rats were fasted before the administration of acetaminophen, thereby increasing the stress on the glutathione pool, exogenous N-acetylcysteine significantly increased the formation of the acetaminophen-glutathione adduct from 57 to 105 nmol/min per 100 g. Although the excretion of acetaminophen sulfate increased from 85+/-15 to 211+/-17 mumol/100 g per 24 h after N-acetylcysteine, kinetic simulations showed that increased sulfation does not significantly decrease formation of the toxic metabolite. Reduction of the benzoquinoneimine by N-acetylcysteine should result in the formation of N-acetylcysteine disulfides and glutathione disulfide via thiol-disulfide exchange. Acetaminophen alone depleted intracellular glutathione, and led to a progressive decrease in the biliary excretion of glutathione and glutathione disulfide. N-Acetylcysteine alone did not affect the biliary excretion of glutathione disulfide. However, when administered after acetaminophen. N-acetylcysteine produced a marked increase in the biliary excretion of glutathione disulfide from 1.2+/-0.3 nmol/min per 100 g in control animals to 5.7+/-0.8 nmol/min per 100 g. Animals treated with acetaminophen and N-acetylcysteine excreted 2.7+/-0.8 nmol/min per 100 g of N-acetylcysteine disulfides (measured by high performance liquid chromatography) compared to 0.4+/-0.1 nmol/min per 100 g in rats treated with N-acetylcysteine alone. In conclusion, exogenous N-acetylcysteine does not form significant amounts of conjugate with the reactive metabolite of acetaminophen in the rat in vivo but increases glutathione synthesis, thus providing more substrate for the detoxification of the reactive metabolite in the early phase of an acetaminophen intoxication when the critical reaction with vital macromolecules occurs.
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NAC prevents toxicity by acting as a glutathione precursor and increasing glutathione availability.
“NAC prevents toxicity by serving as a glutathione precursor, leading to increased glutathione availability (116).”
From Paracetamol: New Vistas of an Old Drug (2006) · cites this paper as [116]
Acetylcysteine is an effective antidote for paracetamol overdose.
“Acetylcysteine is an effective antidote, however despite its use hepatotoxicity and many deaths still occur.”
From Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease (2023) · cites this paper as [96]
NAC restores glutathione by replenishing cysteine, the rate-limiting factor for glutathione synthesis.
“NAC restores glutathione by replenishing cysteine, the ratelimiting factor for glutathione synthesis [96,97].”
From Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease (2023) · cites this paper as [96]
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- Authors
- Lauterburg, B. H., Corcoran, G. B., & Mitchell, J. R.
- Affiliations
- Baylor College of Medicine (US)
- ORCID
- Corcoran, George B.
- Venue
- Journal of Clinical Investigation
- Published
- 1983-04-01
- Volume
- 71
- Issue
- 4
- Pages
- 980-991
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC436956
- OpenAlex
- W2099922198
- Cited by
- 358
- References
- 37
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 6 · 2023: 11 · 2022: 7 · 2021: 11 · 2020: 13 · 2019: 8 · 2018: 15 · 2017: 11 · 2016: 16 · 2015: 13 · 2014: 15 · 2013: 14 · 2012: 5
- FWCI
- 9.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Emergency Medicine › Poisoning and overdose treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- INE, acetaminophen hepatotoxicity, acetaminophen overdose, N-acetyl-p-benzoquinone imine, glutathione depletion, glutathione synthesis, mercapturic acids
- MeSH terms
- Acetaminophen, Acetylcysteine, Animals, Bile, Glucuronates, Glutathione, Male, Rats, Inbred Strains, Sulfates, Rats, Chemical and Drug Induced Liver Injury
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