Acetaminophen liver necrosis caused

The finding that cysteine can prevent the liver necrosis caused by acetaminophen in mice (17) led to the possibility that thio compounds might be useful as antidotes, provided that they are administered while the acetaminophen is being metabolized. Unfortunately, cysteine is a rather ineffective antidote except when it is administered intraperitoneally because it is incorporated into protein by all tissues of the body and thus is subject to a kind of first pass effect by these tissues. Most of the emphasis, therefore, has been toward the development of antidotes that serve as precursors of cysteine (such as methionine and N-acetylcysteine) and thus of glutathione or as alternative nucleophiles that combine with the chemically reactive metabolite. 

N-Acetylcysteine also prevents the liver necrosis caused by acetaminophen in animals and man (45,46). But... 

A pattern of liver necrosis similar to that caused by bromobenzene is observed in patients who ingest massive doses of acetaminophen (Table 16.2). This toxic reaction also has been produced experimentally in mice and rats and is thought to occur in two phases. An initial metabolic phase in which acetaminophen is converted to a reactive iminoquinone metabolite is followed by an oxidation phase in which an abrupt increase in mitochondrial permeability, termed mitochondrial permeability transition (MPT), leads to the release of superoxide and the generation of oxidizing nitrogen and peroxide species that result in hepatocellular necrosis (13, 14). 

Liver injury that results in fulminant hepatic necrosis and acute hver failure is relatively rare. Wheu it occurs, death results iu days or weeks in nearly 80% of cases. Any potential hepatotoxic agent (e.g., acetaminophen) can be responsible, although viral hepatitis is the most common cause worldwide, especially HB V (1 % of patieuts with acute hepatitis B develop fuhniuaut hepatitis). " Fulmiuaut hepatitis caused by HAV occasiouaUy occurs acute liver failme caused by HCV is rare. ... 

As the dose of acetaminophen was increased, the incidence and severity of the liver necrosis in mice was increased ( ). However, an increase in toxicity would be expected to occur regardless of the mechanism of toxicity. Thus, the apparent correlation between the increase in covalent binding and the incidence of toxicity based solely on changes in the dose (12,17) is only trivial and does not indicate whether the toxicity is caused by the parent compound, the chemically reactive metabolite or some other metabolite. 

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. 

Hepatic necrosis can be classified by the zone of the liver tissue affected. Xenobiotics, such as acetaminophen or chloroform, that undergo bioactivation to toxic intermediates cause necrosis of the cells surrounding the central veins (centrilobular) because the components of the cytochrome P450 system are found in those cells in abundance. At higher doses or in the presence of agents that increase the synthesis of cytochrome P450 (inducers), the area of necrosis may incorporate the... 

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... 

Much is known about the biochemical toxicology of hepatotoxicants, yet much remains to be learned. Hepatotoxicity resulting in either cell necrosis, fibrosis, or fatty infiltration is known to be a widespread phenomenon, potentially of importance to human health. It is caused by numerous drugs and environmental agents, and its incidence is expected to increase as confounding viral liver disease becomes more prevalent. Much is known about mechanisms based upon comprehensive studies with a few prototypical chemicals—namely, CCb, ethanol and acetaminophen—which support a convergence of varied primary effects on the ultimate failure of mitochondrial function and Ca2+ homeostasis. The extensive metabolic activity of the liver exposes its cells to a continuous flux of prooxidants. The importance of metabolic activation for the production of reactive metabolites is well-... 

Centrolobular necrosis is often a dose-related, predictable reaction secondary to drugs such as acetaminophen however, it also can be associated with idiosyncratic reactions, such as those caused by halothane. Also called direct or metabolite-related hepatotoxic-ity, centrolobular necrosis is usually the result of the production of a toxic metabolite (see Fig. 38-1). The damage spreads outward from the middle of a lobe of the liver. 

Acetaminophen is metabolized mainly by liver glucuronyl transferase to form the inactive conjugate. A minor pathway (via P450) results in formation of a reactive metabolite (N-acetylbenzoquinoneimine) that is inactivated by glutathione (GSH). In overdose situations, the finite stores of GSH are depleted. Once this happens, the metabolite reacts with hepatocytes, causing nausea and vomiting, abdominal pain, and ultimately liver failure due to centrilobular necrosis. Chronic use of ethanol enhances liver toxicity via induction of P450. 

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