Paracetamol, liver necrosis

The study of receptors has not featured as prominently in toxicology as in pharmacology. However, with some toxic effects such as the production of liver necrosis caused by paracetamol, for instance, although a dose-response relation can be demonstrated (see chap. 7), it currently seems that there may be no simple toxicant-receptor interaction in the classical sense. It may be that a specific receptor-xenobiotic interaction is not always a prerequisite for a toxic effect. Thus, the pharmacological action of volatile general anesthetics does not seem to involve a receptor, but instead the activity is well correlated with the oil-water partition coefficient. However, future detailed studies of mechanisms of toxicity will, it is hoped, reveal the existence of receptors or other types of specific targets where these are involved in toxic effects. 

Paracetamol is a widely used analgesic, which causes liver necrosis and sometimes renal failure after overdoses in many species. The half-life is increased after overdoses because of impaired conjugation of the drug. Toxicity is due to metabolic activation and is increased in patients or animals exposed to microsomal enzyme inducers. The reactive metabolite (NAPQI) reacts with GSH, but depletes it after an excessive dose and then binds to liver protein. Cellular target proteins for the reactive metabolite of paracetamol have been detected, some of which are enzymes that are inhibited. Therefore, a number of events occur during which ATP is depleted, Ca levels are deranged, and massive chemical stress switches on the stress response. 

Intrinsic toxicity Direct toxicity Yes Yes Hours Usually necrosis Acute liver failure Paracetamol... 

Boyd EM, Bereczky GM (1966) Liver necrosis from paracetamol. Br J Pharmacol Chemothta-26 606-614... 

Dahlin DC, Miwa GT, Lu AY, Nelson SD (1984) N-acetyl-p-benzoquinone imine a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci USA 81 1327-1331 Davem TJ 2nd, James LP, Hinson JA, Poison J, Larson AM, Fontana RJ, Lalani E, Munoz S, Shakil AO, Lee WM (2006) Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 130 687-694 Davidson DG, Eastham WN (1966) Acute liver necrosis following overdose of paracetamol. Br Med J 5512 497 99... 

Hepatotoxicity does not occur at recommended doses of acetaminophen. Administration of 2 g, or twice the recommended dose, of intravenous paracetamol in healthy subjects has been shown to stay far below the threshold of hepatotoxicity. When ingested at high doses, acetaminophen is metabolized to JV-acetyl-p-benzoquinone-imine (NAPQI). NAPQI is rapidly conjugated with glutathione to a nontoxic compound. The depletion of glutathione results in the accumulation of NAPQI that is responsible for liver injury. Acetaminophen has a narrow therapeutic window and even minor overdoses may cause severe hepatic injury. Liver necrosis occurs at 7.5-10 g of acetaminophen. 

Paracetamol overdose is most likely to cause hepatic necrosis and to a lesser extent renal necrosis. Hepatic necrosis is maximal within 3-4 hours of ingestion and may lead to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema and death. Acetylcysteine tends to protect the liver if given within 10-12 hours of paracetamol poisoning. The maximum adult dose of paracetamol is 4 g in 24 hours. 

Overdoses of paracetamol can be very dangerous, as the drug has a narrow therapeutic index and may cause hepatic and renal necrosis. Nausea, vomiting, lethargy, and sweating are the early overdose symptoms. Paracetamol must be given with caution in alcoholics and patients with liver and kidney damage. 

Acetaminophen (paracetamol, 4-hydroxyacetanilide, APAP), a commonly used analgesic drug, causes centrilobular hepatic necrosis upon overdosage. APAP displays toxicity characteristics that demonstrate, very clearly, dependence upon GSH for protection. Hepatotoxicity, including liver failure, often occurs when APAP is... 

Domperidone may be the antiemetic of choice, but as the patient has very little metabolic and synthetic liver function, owing to massive hepatocellular necrosis secondary to the hepatotoxic effects of the paracetamol overdose, accumulation of the domperidone may occur. However, it may be of benefit as a pro-kinetic agent. 

Fig. 20.3 Centrilobular, two-week-old liver cell necrosis resulting from paracetamol intoxication (HE)...

Paracetamol is metabolised in the liver, where it is converted to a highly toxic intermediate that is normally detoxified by conjugation with glutathione. In overdose, this detoxification mechanism is overwhelmed and the free toxic metabolite causes hepatitis and necrosis, which can prove fatal. 

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Weis M, Kass GE, Orrenius S (1994) Further characterization of the events involved in mitochondrial Ca2+ release and pore formation by prooxidants. Biochem Pharmacol 47 2147—2156 Welch KD, Reilly TP, Bourdi M, Hays T, Pise-Masison CA, Radtmovich MF, Brady JN, Dix DJ, Pohl LR (2006) Genomic identification of potential risk factors during acetaminophen-induced liver disease in susceptible and resistant strains of mice. Chem Res Toxicol 19 223-233 Wendel A, Feuerstein S, Konz KH (1979) Acute paracetamol intoxication of starved mice leads to lipid peroxidation in vivo. Biochem Pharmacol 28 2051-2055 Yamada Y, Kirillova I, Peschon JJ, Fausto N (1997) Initiation of liver growth by tumor necrosis factor deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc Natl Acad Sci USA 94 1441-1446... 

Dear, J.W., et al., Letter to the editor early detection of paracetamol toxicity using circulating liver microRNA and markers of ceU necrosis. BrJ Clin Pharmacol, 2013. doi 10.1111/bcp.l2214. 

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