Centrilobular hepatic necrosis

Administration of a PCB mixture (mean chlorine content 54%) twice a week for 6 weeks via a stomach tube to rats at relatively low dose levels led to histopathologic changes in the liver, increases in cholesterol and triglyceride levels, and serum enzyme increases. At the 2mg/kg dose, centrilobular hepatic necrosis and elevated cholesterol levels were observed. Increases in bilirubin and triglyceride levels occurred only at 50mg/kg and increases in SCOT (AST) and SGPT (ALT) only at doses above 50mg/kg. ... 

NMOR causes centrilobular hepatic necrosis in rats. Hepatocellular carcinomas were observed in 14 of 16 rats administered NMOR in the drinking water at doses of 8mg/kg body weight/day for life. Continuous oral exposure of Sprague-Dawley rats to 6, 12, or 24mg/kg body weight resulted in a dose-... 

Toxicity. Atractyloside, a diterpenoid glycoside that occurs naturally in plants, may be present at levels as high as 600 mg/kg of dried plant material. Gonsumption of plants containing atractyloside or carboxyatractyl-oside has caused fatal renal proximal tubule necrosis and/or centrilobular hepatic necrosis in man and farm animals. Although pure atractyloside and crude plant extracts disrupt carbohydrate homeostasis and induce similar pathophysiological lesions in the kidney and liver, it is also possible that the toxicity of atractyloside may be confounded by the presence of other natural constituents in plants. Atractyloside competitively inhibits the adenine nucleoside... 

APAP, although a safe drug in therapeutic doses, can lead to severe and potentially lethal liver and kidney injury in cases of overdose. Liver injury involves a characteristic centrilobular hepatic necrosis. The centrilobular region is rich in metabolic enzymes, such as the CYP family of isozymes. CYP2E1 is the predominant P450 isozyme in catalyzing the oxidation of APAP to a reactive intermediate, N-acetyl-p-benzoquinonimine (NAPQI), which possesses an electrophilic carbon that will covalently bind to cellular proteins [35], as shown in Scheme 3.2. 

Carbon tetrachloride is a simple molecule which, when administered to a variety of species, causes centrilobular hepatic necrosis (zone 3) and fatty liver. It is a very lipid-soluble compound and is consequently well distributed throughout the body, but despite this, its... 

Paracetamol (acetaminophen) is a widely used analgesic and antipyretic drug that is relatively safe when taken at prescribed therapeutic doses. However, it has become increasingly common for overdoses of paracetamol to be taken for suicidal intent. In the United Kingdom, for example, around 200 deaths a year result from overdoses of paracetamol. This has prompted some to call for changes in its availability, with newspaper headlines such as "Doctors demand curbs on killer paracetamol" (Sunday Times, London, 14th November, 1993). When taken in overdoses, paracetamol causes primarily centrilobular hepatic necrosis, but this may also be accompanied by renal damage and failure. 

Bromobenzene is a toxic industrial solvent that causes centrilobular hepatic necrosis in experimental animals. It may also cause renal damage and bronchiolar necrosis. The study of the mechanism underlying the hepa to toxicity of bromobenzene has been of particular importance in leading to a greater understanding of the role of GSH and metabolic activation in toxicity. 

Bromobenzene is a toxic industrial solvent that is known to produce centrilobular hepatic necrosis through the formation of reactive epoxides. Figure 14.6 summarizes... 

Baerg, R.D. Kimberg, D.V. Centrilobular hepatic necrosis and acute renal failure in "solvent sniffers." Ann Int Med, 1970 73 713-720... 

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... 

FIGURE 37.2. Metabolism and mechanism of acetaminophen toxicity. Bioactivation of acetaminophen by P450 enzymes results in the formation of the reactive intermediate (NAPQI) which forms covalent protein adducts with glutathione which is then converted to mercapturic acid. When the amount of the reactive metabolite formed exceeds the glutathione available for binding, the excess metabolite binds to tissue molecules resulting in centrilobular hepatic necrosis. 

The oral route of exposure in dogs to high concentrations leads to vomiting, diarrhea, and death. The major histopathological findings were centrilobular hepatic necrosis. The necrosis included the central hepatic veins and their respective tributaries. Bromobenzene was not found to be mutagenic in the Ames assay. 

In an acute overdose situation, sulfate stores are depleted, shifting more drug through the cytochrome system, thereby depleting the available glutathione used to detoxify the reactive metabolite. The reactive metabolite, NAPQI, then reacts with other hepatocellular sulfhydryl compounds such as those in the cytosol, cell wall, and endoplasmic reticulum. This results in centrilobular hepatic necrosis. Several other mechanisms, such as cytokine release or oxidative stress, also may be initiated by the initial cellular injury. ... 

Carbon tetrachloride is a simple molecule which, when administered to a variety of species, causes centrilobular hepatic necrosis... 

Paracetamol causes centrilobular hepatic necrosis in various species, although there are substantial species differences in susceptibility (figure 7,9). Experimental animal species susceptible to paracetamol have been used to study the mechanism underlying the hepatotoxicity. It was found that the degree of hepatic necrosis caused by paracetamol was markedly increased by pretreatment of animals with microsomal enzyme inducers and, conversely,... 

Bromobenzene is an industrial solvent and environmental pollutant, which causes centrilobular hepatic necrosis in rats and mice (Casini et al. 1985 Jollow et al. 

Liver Acetaminophen Increased mortality, increased serum transaminase levels, greater depletion of GSH, increased tissue lesions, increased centrilobular hepatic necrosis Chan et al. (2001) Enomoto et al. (2001)... 

Although considered safe at therapeutic doses, at higher doses, acetaminophen produces a centrilobular hepatic necrosis that can be fatal. Acetaminophen poisoning accounts for approximately one-half of all cases of acute liver failure in the United States and Great Britain today (Larson et al. 2005 Ostapowicz et al. 2002) Annually, it accounts for a very high percentage of inquiries to poison control centers and deaths (Litovitz et al. 2002). The direct costs of acetaminophen overdose have been estimated to be as high as US 87 million annually (Bond and Novak 1995). 

DeLeve and coworkers (DeLeve et al. 1997) examined the possibility that sinusoidal hepatic endothelial cells may metabolize acetaminophen in vitro and that this may be important in toxicity. Previous data indicated that hepatic endothelial cells contain CYP enzymes (Oesch and Steinberg 1987 Steinberg et al. 1990), and that activation of acetaminophen by CYP enzymes in endothelial cells may produce toxicity. Endothelial cells were isolated from two strains of mice. Acetaminophen was not toxic to cultured endothelial cells from Swiss Webster mice but was toxic to cultured endothelial cells from C3H-HEN mice. Glutathione was depleted in the sensitive endothelial cells before the development of toxicity whereas glutathione was not depleted in endothelial cells from the Swiss Webster mice. Addition of glutathione to the incubation or the CYP inhibitor aminobenzo-triazole inhibited development of toxicity in the C3H-HEN cells. However, the two strains of mice appeared to be equally sensitive to the centrilobular hepatic necrosis produced by acetaminophen in vivo. 

Centrilobular hepatic necrosis by single doses of coumarin (1,2-benzopyrone, ds-o-coumarinic acid lactone) have been reported in the rat (Lake 1984, Lake et al. 1989, Fentem et al. 1992), whereas chronic administration resulted in bile duct lesions (Hagan etal. 1967, Cohen 1979, Evans etal. 1989). The mechanism of acute coumarin-induced hepatotoxicity in the rat has been investigated by comparing the effects of coumarin with those of a number of methyl-substituted coumarin derivatives (Lake etal. 1994). Coumarin administration produced dose-related hepatic necrosis and a marked elevation of plasma alanine aminotransferase and aspartate aminotransferase activities. In contrast, non of the coumarin derivatives examined produced either hepatic necrosis or elevated plasma transaminase activities. Coumarin reduced hepatic microsomal ethylmorphine N-demethylase and 7-ethoxycoumarin 0-deethylase activities, whereas one or both mixed function oxidases appeared to be induced by treatment with 3,4-dimethylcoumarin, 4-methylcoumarin, 3-methyloctahydrocoumarin and 4-methyloctahydrocoumarin. These results provides an evidence that acute coumarin-induced hepatotoxicity in the rat is due to the formation of a coumarin 3,4-epoxide intermediate. 

Acute multifocal centrilobular hepatic necrosis is typical of day pigeon poisoning ofsvrine. 

Paracetamol overdosage is an increasing problem in some countries and is often complicated by acute centrilobular hepatic necrosis which may be fatal (215 —224, 225, 226 —230, 257 ). The current importance of the phenomenon naturally results from the trend to replace other simple analgesics by paracetamol, especially in Britain. 

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