Necrosis hepatocytes

Animals studies indicate that exposure to relatively high 1,1,1-trichloroethane concentrations in air (>1,000 ppm) or high oral doses (>1,334 mg/kg) are required to produce liver injury (Adams et al. 1950 Bruckner 1983 Calhoun et al. 1981 McNutt et al. 1975 Torkelson et al. 1958 Tyson et al. 1983). Effects observed in animals include necrosis, fatty change, increased liver weight, and changes in liver and serum enzyme levels. These effects are reversible and subside after termination of exposure (in the case of necrosis, hepatocytes in the proximity of the killed cells proliferate and replace them). 

Acute Liver Damage Several compounds (e.g., dimethyl iiitrosoamine, carbon tetrachloride, and thioacetamide) cause necrosis of hepatocytes by inhibiting pro tein syndiesis at the translational level, i.e., by inhibiting the addition of new amino adds into the protein chain being sjTithetized. This is not, however, the only mechanism. Ethioiiine is a compound which inhibits protein synthesis bur doe not induce... 

Accumulation of lipids in the liver (steatosis) is one possible mechanism for liver toxicity. Several compounds causing necrosis of hepatocytes also cause steatosis. There are, however, some doubts that steatosis would be the primary cause of liver injury. Several compounds cause steatosis (e.g., puro-mycin, cycloheximide) without causing liver injury. Most of the accumulated lipids are triglycerides. In steatosis, the balance between the synthesis and excretion of these lipids has been disturbed (see Table 5.13). 

The histopathological examination of mice liver performed after a single dose of dibromobenzenes shows that 2 and 2 isomers resulted in zonal coagulative or haemorragic necrosis. It affected from 25-50 % to over 50 % of the liver parenchyma (i.e. 4-5 arbitrary units). 4 caused necrosis of only individual hepatocytes. 

Bromobenzene, similarly to acetaminophen, is considered as model compound in liver necrosis (refs. 9-11, 20, 21). After the administration of these compounds, a considerable decrease in GSH levels, an increase in GTP activity in the serum and, histopathologically, necrosis of hepatocytes are observed. 

Flaviviruses Yeiiow fever virus Spherical particles 40 nm in diameter with an inner core surrounded by an adherent lipid envelope The virus is spread to humans by mosquito bites the liver is the main target necrosis of hepatocytes leads to jaundice and fever... 

Portal infusion of NAPQl into rats and mice produces necrosis in the periportal region (unpublished results quoted by Nelson, 1990). Studies of cultured hepatocytes sensitized to paracetamol by the induction of cytochrome P450 by 3-methylcholanthrene have shown that paracetamol-induced cytotoxicity was dependent on ROM generation (Gerson et al., 1985). 

Chevalier S et al. Proteomic analysis of differential protein expression in primary hepatocytes induced by EGF, tumour necrosis factor alpha or the peroxisome pro-liferator nafenopin. Eur J Biochem 2000 267 4624-4634. 

Liver necrosis is another concern following hexachloroethane exposure. Hexachloroethane is metabolized in the centrilobular area of the liver by way of the microsomal mixed function oxidase system. The relatively nonpolar pentachloroethyl free radical is an intermediate in this pathway. The reaction of the free radical with unsaturated lipids in the cellular or organelle membranes could contribute to hepatocyte damage and necrosis. 

This MRL for mirex was derived using a NOAEL of 0.075 mg/kg/day for dose-dependent hepatic changes from a study by NTP (1990). The dose-dependent changes included increased fatty metamorphosis (cytoplasmic vacuoles consistent with intracellular fat accumulation) and necrosis of hepatocytes (focal and/or centrilobular) in F344/N rats of both sexes at a dose of 0.7 mg/kg/day... 

Signaling pathways. (From Bahjat, F.R., Characterization and Genetic Analysis of the Resistance of Nonobese Diabetic Mice to Tumor Necrosis Factor-Alpha Mediated Hepatocyte Apoptosis and Lethality, A dissertation presented to the Graduate School of the University of Florida in partial fulfillment of the requirement for the degree of doctor of philosophy. University of Florida, 2002. Reproduced with permission.)... 

Matthews, N., Neale, M.L., Jackson, S.K., and Stark, J.M., 1987, Tumor cell kilhng by tumor necrosis factor inhibition by anearobiotic condition, free-radical scavengers and inhibitors of arachidonate metabolism. Immunology 62 153-155 Miller, M.G., Rodgers, A., and Cohen, G.M., 1986, Mechanisms oftoxicity of naphthoquinones to isolated hepatocytes. Biochem. Pharmacol. 35 1177-1184 Minko, T., Kopeckova, P., and Kopecek, J., 1999, Comparison ofthe anticancer effect of free and HPMA copolymer-bound adtiamycin in human ovarian carcinoma cells. Pharmaceut. Res. 16 986-996... 

Monney, L., Ohvier, R., Otter, 1., Jansen, B., Poirier, GG., and Bomer, C., 1998, Role ofan acidic compartment in tumor-necrosis-factor-a-induced production of ceramide, activation of caspase-3 and apoptosis. Eur. J. Biochem. 251 295-303 Morrison, H., Jemstrom, B., Nordenskjdld, M., Thor, H., and Orrenius, S., 1984, Induction of DNA damage by menadione (2-methyl-l,4-naphthoquinone) in primary cultures of rat hepatocytes. Biochem. Pharmacol. 33 1763-1769 Neuzil, J., Svensson, 1., Weber, T, Weber, C., and Brunk, U.T., 1999, alpha-tocopheryl succinate-induced apoptosis in Jurkat T cells involves caspase-3 activation, and both lysosomal and mitochondrial destabilisation. FEES Lett. 445 295-300 Ngo, E.O., Nutter, L.M., Sura, T., and Gutierrez, P. L., 1998, Induction ofp53 by the... 

Liver toxicity related to 1,2-dibromoethane depends on the metabolic pathway utilized and the amount of damage induced in cellular protein and membrane structures. Humans exposed to low levels of 1,2-dibromoethane are at potential risk of having toxic events occurring within hepatocytes whether these effects will be subcellular or result in cell necrosis may depend on internal dose and a variety of factors. Liver damage that is severe enough to cause clinical disease in humans from low-level exposure is unlikely. 

F (centrilobuiar hepatocyte necrosis and severe diffuse vacuolar degeneration of midzonal and periportal hepatocytes)... 

F (increased relative liver weights hepatocyte lipid vacuolization scattered individual hepatocyte necrosis significant increase in hepatic LI)... 

At necropsy, livers were removed, weighed, examined macroscopically, and prepared for microscopic evaluation. Exposure to 90 ppm chloroform resulted in increased relative liver weights. Female mice exposed to chloroform for 4 days experienced a dose-dependent mild response of uniform hepatocyte lipid vacuolization. Scattered individual hepatocyte necrosis also occurred in a dose-dependent manner. 

In male rats, swelling and mild centrilobular vacuolation was observed only in the livers of rats exposed to 271 ppm. Necrosis was minimal and confined to individual hepatocytes immediately adjacent to the central vein livers were dark red and congested. The hepatocyte LI in rats were increased only at 101 and 271 ppm, 3- and 7-fold over controls, respectively. An acute-duration inhalation MRL of 0.1 ppm was based on the NOAEL of 3 ppm for hepatic effects in mice. More information on this MRL and how it was derived is located in the footnote to Table 2-1, Section 2.5 in Appendix A this profile. 

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