Necrosis centrilobular

Inomata, T., Rao, G.A. and Tsukamoto, H. (1987). Lack of evidence for increased lipid peroxidation in ethanol-induced centrilobular necrosis of rat liver. Liver 7, 233-239. 

Tsukamoto, H. and Bacon, B.R, (1987). Status of pro and antioxidants in ethanol-induced centrilobular necrosis. Heptology 7, 1078. 

Hepatic reperfusion injury is not a phenomenon connected solely to liver transplantation but also to situations of prolonged hypoperfusion of the host s own liver. Examples of this occurrence are hypovolemic shock and acute cardiovascular injur) (heart attack). As a result of such cessation and then reintroduction of blood flow, the liver is damaged such that centrilobular necrosis occurs and elevated levels of liver enzymes in the serum can be detected. Particularly because of the involvement of other organs, the interpretation of the role of free radicals in ischaemic hepatitis from this clinical data is very difficult. The involvement of free radicals in the overall phenomenon of hypovolemic shock has been discussed recently by Redl et al. (1993). More specifically. Poll (1993) has reported preliminary data on markers of free-radical production during ischaemic hepatitis. These markers mostly concerned indices of lipid peroxidation in the serum and also in the erythrocytes of affected subjects, and a correlation was seen with the extent of liver injury. The mechanisms of free-radical damage in this model will be difficult to determine in the clinical setting, but the similarity to the situation with transplanted liver surest that the above discussion of the role of XO activation, Kupffer cell activation and induction of an acute inflammatory response would be also relevant here. It will be important to establish whether oxidative stress is important in the pathogenesis of ischaemic hepatitis and in the problems of liver transplantation discussed above, since it would surest that antioxidant therapy could be of real benefit. 

Weanlings died from extensive centrilobular necrosis... 

Intratracheal injection of Pb carbonate at doses of 50-135 mg Pb/kg BW for 29 to 362 days 73% dead (11/15) with total dose of 1250-7800 mg lead. Before death, some animals lost weight, became increasingly aggressive, had hepatic centrilobular necrosis, were uncoordinated and weak, and had convulsions the blood had up to 62 mg Pb/L 22... 

The liver is sensitive to hexachloroethane following both acute and longer term exposure scenarios. Evidence of effects on the liver include increased weight and centrilobular necrosis in rats and rabbits and increased serum levels of liver enzymes in sheep. There can also be fatty degeneration of the tissues and hemorrhage when damage is severe. 

Di-tt-octylphthalate has been shown to be a mild liver toxin at high doses in acute- and intermediate-duration studies in rodents. While the mechanism of action for these hepatic effects is not known, di-w-octylphthalate does not appear to behave like other phthalate esters such as di(2-ethylhexyl)phthalate, which have been shown to be hypolipidemic peroxisome proliferators. Instead, the liver changes associated with exposure to di- -octylphthalate are characterized by marked centrilobular accumulation of fat and loss of glycogen, accompanied by reduced glucose-6-phosphatase activity and some centrilobular necrosis. 

Hepatotoxicity, characterized histologically by centrilobular necrosis, and elevated hepatic enzymes in serum were reported in separate studies in which laboratory animals were exposed to phenol in air at concentrations 26 ppm (Dalin and Kristoffersson 1974 Deichmann et al. 1944). Hepatic effects were not observed in monkeys, rats, or mice exposed to 5 ppm phenol in air continuously for 90 days (Sandage 1961). Hepatic effects have also not been observed in rodents following oral exposure to phenol (Berman et al. 1995 Hsieh et al. 1992 Jones-Price et al. 1983a, 1983b NCI 1980). 

Using light microscopy, Broda et al. (1976) did not observe hepatocellular fatty change in livers of rats exposed by gavage to 110 mg/kg 1,2-dibromoethane in olive oil. Rats developed centrilobular dilatation within 8 hours after exposure, hepatocellular degeneration within 17 hours after exposure, and frank centrilobular necrosis 22 hours after 1,2-dibromoethane exposure. 

No studies were located in humans regarding the distribution of 1,2-dibromoethane after oral exposure. In humans intentionally ingesting 1,2-dibromoethane, kidney lesions and centrilobular necrosis of the liver were found (Olmstead 1960 Saraswat et al. 1986). This is indirect evidence of distribution of 1,2-dibromoethane. The tissue distribution of 1,2-dibromoethane has been studied in rats following exposure by the oral route. Although retention was limited, the kidneys, liver, and spleen appear to retain the highest amounts of the administered dose (Plotnick et al. 1979) as illustrated in Table 2-4. Rats received an oral dose of 15 mg/kg/day of labeled 1,2-dibromoethane in corn oil. Twenty-four hours later 3% of radioactivity was detected in fat, brain, kidney, liver, spleen, testes, blood, and plasma, 72.38% in the urine, and 1.65% in the feces (Plotnick et al. 1979). By 48 hours after administration, 73% of the radiolabeled dose was accounted for in the urine, 1.1% in the liver, and 2.4% in the feces. Total recovery was 77.8% of the administered radioactivity. 

Mouse once Hepatic 35 (midzonal fatty changes) 350 (centrilobular necrosis) Jones et al. 1958... 

Upon autopsy, centrilobular necrosis was observed in the women who died however, the hepatotoxicity was associated with exhaustion from prolonged delivery, starvation, and dehydration, indicating improper... 

Landon EJ, Naukam RJ, Sastry BVR. 1986. Effects of calcium channel blocking agents on calcium and centrilobular necrosis in the liver of rats treated with hepatotoxic agents. Biochem Pharmacol 35 697-705. 

Histopathologic lesions of the liver have been demonstrated in several oral studies in rodents dosed at higher levels of 1,4-dichlorobenzene. Cloudy swelling and centrilobular necrosis were observed in the livers of rats that received 1,4-dichlorobenzene at 500 mg/kg/day for 4 weeks (Hollingsworth et al. 1956). Thirteen-week studies have resulted in degeneration and necrosis of hepatocytes in rats that received doses of 1,200 mg/kg/day and above and in mice, hepatocellular degeneration was observed at... 

Large oral doses of DDT in rats caused focal and centrilobular necrosis of the liver. However, in clinical evaluation and laboratory studies of 31 workers exposed to equivalent oral intakes of 3.6-18 mg daily for an average of 21 years, there was no evidence of hepatotoxicity an observed increase in activity of hepatic microsomal enzymes was not accompanied by clinical evidence of detriment to general health. ... 

Rats died from exposure to 977 ppm for 7 hours but survived when exposed for only 2 hours animals survived exposure to 539ppm for 3 hours but at necropsy showed marked centrilobular necrosis of the liver, as well as cloudy swelling of the tubular epithelium of the... 

Guinea pigs exposed to 5 0,000 ppm for 98 minutes died within an hour after exposure. Exposure to 24,000 ppm for 30 minutes was fatal within 3 days at autopsy, findings were pulmonary edema and centrilobular necrosis of the liver exposure to 3200ppm for 9 hours produced lung irritation, and death occurred after 1-5 days. The 1-hour LCso was 27,000ppm for male rats and 16,200ppm for mice. ... 

Repeated exposure of rats to an average concentration of 8.9mg/m of a mixture of penta- and hexachloronaphthalene produced jaundice and was fatal the liver showed a marked fatty degeneration and centrilobular necrosis. At 1.16mg/m, minor liver injury still occurred. 

Rats that received a single lethal dose of NDPA showed centrilobular necrosis and fatty degeneration of the liver. Specific doses that caused this effect were not listed, but the oral LD50 was determined to be 480 mg/kg. 

Fatty degeneration and centrilobular necrosis were observed in the livers of mice that died following acute exposure to o-cresol the mean lethal concentration was 178 mg/m. Exposure to 9 mg/m for 4 months interfered with liver function in rats, as shown by increased susceptibility to hexanol narcosis (Uzhdavini et al. 1972). 

As an example, acetaminophen (APAP) in overdose has been used by several groups to identify hepatotoxicity biomarkers in mice. APAP-induced hepatotoxicity is characterized by hepatic centrilobular necrosis and hepatitis. APAP biotransformation by Phase I enzymes leads to the formation of the reactive metabolite N-acetyl-p-benzoquinone (NAPQI), which can deplete glutathione and form adducts with hepatic proteins (see Section 15.2). Protein adduction primes the hepatocytes for cytokines released by activated macrophages (Kupffer cells) and/or destructive insults by reactive nitrogen species. Although necrosis is recognized as the mode of cell death in APAP overdose, the precise mechanisms are still being elucidated [152]. 

In animals, the hepatic effects of inhalation exposure to carbon tetrachloride are much the same as in humans elevated serum enzyme levels, steatosis and centrilobular necrosis progressing to fibrosis. In rats, exposure to concentrations of 10-100 ppm are generally observed to result in mild to moderate signs of liver injury, both after short-term and intermediate exposure (Adams et al. 

The hepatotoxic effects of carbon tetrachloride have been widely studied in animals. Indeed, carbon tetrachloride is used as a model chemical in many laboratory investigations of the basic mechanism of action of hepatotoxic chemicals. Oral exposure to carbon tetrachloride has been observed to result in a wide spectrum of adverse effects on the liver, the most prominent of which are destruction of the smooth and rough endoplasmic reticulum and its associated enzyme activities (Reynolds and Yee 1968), inhibition of protein synthesis (Lutz and Shires 1978), impaired secretion of triglycerides with resultant fat accumulation (Fischer-Nielsen et al. 1991 Recknagel and Ghoshal 1966 Recknagel and Glende 1973 Waterfield et al. 1991), centrilobular necrosis (Blair et al. 1991 Reynolds and Yee 1968 Waterfield et al. 1991 Waterfield et al. 1991 Weber et al. 1992), and eventually fibrosis and cirrhosis (Allis et al. 1990 Bruckner et al. 1986 Fischer-Nielsen et al. 1991 Weber etal. 1992). 

Chloroform Drug purification Hepatic centrilobular necrosis, likely from reactive metabolites... 

In male Wistar rats, coumarin, 3-methylcoumarin or 4-methylcoumarin was administered intraperitoneally at a single dose of 1.03 mmol/kg bw and rats were killed 24 h later. Coumarin produced histological evidence of centrilobular necrosis, while the methyl analogues were much less toxic at equivalent doses. In the same study, these compounds had the same order of cytotoxicity in isolated hepatocytes as that observed in vivo (Femyhough et al, 1994). 

Cottrell et al. (1996) reported that a single oral dose of coumarin produced liver necrosis in mice 200 mg/kg bw coumarin was hepatotoxic to both C3H/He and DBA/2 mice. Hepatotoxicity was characterized by an increase in plasma aminotransferase activity, mild subcapsular linear hepatocyte necrosis and, in some C3H/He mice, centrilobular necrosis. Mice were pretreated with (3-naphthoflavone (80 mg/kg bw), Aroclor 1254 (54, 125 or 162 mg/kg bw) or vehicle alone by intraperitoneal injection for three consecutive days. Twenty-four hours later, a single dose of coumarin (200 mg/kg bw) or vehicle was administered by gavage. Pretreatment with... 

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