Liver necrosis in rat

Burk RF and Lane JM (1979) Ethane production and liver necrosis in rats after administration of drugs and other chemicals. Toxicology and Applied Pharmacology 50 467. 

In dietary liver necrosis in rats, methylmalonic acid is greatly increased in the urine, representing 70 % of total ether-soluble adds instead of 10 % as in normal animals a,a-dimethylsuccinie add is also increased, but to a smaller extent (B3, F6). 

Selenium (Factor 3) prevents liver necrosis in rats... 

Matos HR, Capelozzi VL, Gomes OF, Mascio PD, Medeiros MH. Lycopene inhibits DNA damage and liver necrosis in rats treated with ferric nitrUotriacetate. Arch Biochem Biophys 2001 396 171-177. 

The acute toxicity of chlordane in rats increased when rats were fed protein deficient diets (Boyd and Taylor 1969). Chlordane treatment has also been demonstrated to enhance the hepatotoxic effects produced by carbon tetrachloride in rats, as indicated by its effect on SGPT levels, presumably by inducing the metabolism of carbon tetrachloride to its toxic metabolite (Mahon et al. 1978 Stenger et al. 1975). On the other hand, chlordane provided some protection against carbon tetrachloride-induced liver necrosis in rats, possibly by inducing a type of cytochrome P-450 with diminished ability to metabolize carbon tetrachloride to its toxic metabolite (Mahon et al. 1978). Pretreatment of rats with chlordane accelerated the metabolism of lindane, presumably by the same mechanism (Chadwick et al. 1977). 

Since vitamin E prevents the promotion of liver necrosis in rats by silver, and since this element appears to promote in vivo peroxidation, one of the ways that silver brings about its damaging effects may be by generation of peroxides (reaction 5). It has been proposed that vitamin E functions in inhibiting the formation of peroxides, whereas selenium, as GSH-Px, is involved in the breakdown of peroxides (reaction 6) to the less harmful, alcohols (Hoekstra, 1975). If metals such as mercury or silver inhibit the activity of this enzyme (reaction 7), this could result in tissue damage due to peroxide accumulation, particularly when vitamin E is also absent or low. Evidence has been presented that selenide is an intermediate in GSH-Px synthesis (Sunde and Hoekstra, 1980). Thus, an adequate supply of selenide should generate more GSH-Px (reaction 8) and sele-noamino acids, such as selenocysteine (reaction 9). An adequate supply of selenide would allow the animal to more adequately combat the detrimental effects of heavy metals. Finally, the involvement of tissue sulfhy-dryls in the formation of bis(methylmercuric)selenide is another possible mechanism of heavy metal detoxification by selenium (Iwata et al., 1981 ... 

For a number of years selenium remained a chemical curiosity. In 1873 Smith discovered the unique electrical properties of selenium and brought it to public attention [7]. In the 1930 s selenium was identified as the cause of blind staggers and alkali disease in livestock and it became of interest because of its toxic effects [47]. The role of selenium as an essential element was proposed in 1957 when Schwartz and Foltz [42] determined that selenium was necessary to prevent liver necrosis in rats. Subsequent studies showed selenium was an essential trace element for several animals [32]. 

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. 

Orotic acid added to rat diet also provokes an. excessive biosynthesis of porphyrins in liver, erythrocytes and bone marrow. Administration of adenine monophosphate (AMP) counteracted this effect of orotic acid intoxication [165]. Haemorrhagic renal necrosis in rats, caused by choline deficiency, can be relieved by orotic acid [166], Simultaneous supplementation of the diet with adenine does not influence the protective effect of orotic acid. It has been suggested that orotic acid may lower the body requirement for choline through a metabolic interaction—orotic acid may stimulate the cytidine phosphate choline pathway of lecthin biosynthesis [166]. 

Oral doses of 2.5 ml of a 1 1 v/v mixture in olive oil were fatal to rats. A historical study indicates that exposure of rats to 800-900 ppm for 7 hours/day for six exposures caused hemorrhagic liver necrosis in some of the rats as well as focal necrosis of the kidneys. No deaths occurred from these exposures. 

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). 

No treatment-related gross or histopathological lesions in the liver were observed in rats in the chronic experiment by NTP (1986), but dosed male mice had increased coagulative necrosis and hepatocytomegaly, along with increased incidences of hepatocellular adenomas and carcinomas (see Section 2.2.2.8 on carcinogenicity). Female mice, however, did not have treatment-related lesions in the liver. The highest dose (500 mg/kg/day) is indicated as a NOAEL for liver effects in rats, while the low dose (250 mg/kg/day) is indicated as a LOAEL for non-neoplastic liver lesions in... 

Long-term feeding of hydroquinone to rats led to aplastic anaemia, liver cord-cell atrophy and ulceration of the gastric mucosa. A single high dose was reported to induce renal tubule necrosis in rats (lARC, 1977). 

In 1957, Schwartz and associates showed that the toxic element selenium was also a nutritional factor essential for prevention of the death of liver cells in rats.527 Liver necrosis would be prevented by as little as 0.1 ppm of selenium in the diet. Similar amounts of selenium were shown to prevent a muscular dystrophy called "white muscle disease" in cattle and sheep grazing on selenium-deficient soil. Sodium selenite and other inorganic selenium compounds were more effective than organic compounds in which Se had replaced sulfur. Keshan disease, an often fatal heart condition that is prevalent among childen in Se-deficient regions of China, can be prevented by supplementation of the diet with NaSe03.528 Even the little crustacean "water flea" Daphnia needs 0.1 part per billion of Se in its water.529... 

Grasso P, Abraham R, Hendy R, et al. 1969. The role of dietary silver in the production of liver necrosis in vitamin E-deficient rats. Exp Mol Pathol 11 186-199. 

The high mortality rates in pregnant rats may indicate a parturition-related sensitivity to the toxic effects of white phosphorus. Upon histopathological evaluation of selected tissues (heart, liver, kidneys, uterus, ovaries, and testes/epididymides), the only finding considered treatment related was an increased incidence of centrilobular liver necrosis in 8/30 treated females (Bio/dynamics 1991). 

Impila causes massive centrilobular liver necrosis with hypoglycemia and liver failure. It also causes acute tubular necrosis [16,17]. Atractyloside is a component in the root of the impila and it is this substance, which has been demonstrated to cause acute tubular necrosis in rats [17]. 

The role of selenium in human medicine has been reviewed. Animal studies in the 1950s demonstrated the nutritionally beneficial, effects of selenium by showing that there was a selenium-responsive liver necrosis in vitamin E-deficient rats. There are important selenium-dependent diseases in farm animals, such as white muscle disease in sheep and cattle, and myopathy of cardiac and skeletal muscle in lambs and calves. In these animals, some cause of oxidative stress, such as increased physical activity or vitamin E deficiency—together witli dietary selenium deficiency—is required to elicit the disease. 

Liver effects have been reported in both humans and animals exposed to nitrobenzene. Hepatic enlargement and tenderness, jaundice, and altered serum chemistries were reported in a 47-year-old woman who had been occupationally exposed to nitrobenzene for 17 months (Ikeda and Kita 1964). The authors considered these changes to be related to increased destruction of hemoglobin and enlargement of the spleen. Liver effects observed in animals following nitrobenzene exposure are hepatocyte necrosis in rats (Medinsky and Irons 1985) and increased liver weight, hepatocyte hyperplasia, and multinucleated hepatocytes in mice (Hamm 1984). Hepatic effects have not been reported in oral studies. Dermal painting studies in mice resulted in diffuse necrosis in the outer two- thirds of the lobules of the liver (Shimkin 1939). 

Schwarz, K., and Mertz, W., Terminal phase of dietary liver necrosis in the rat (Hepatogenic hypoglycemia). Metabolism Clin, and Exptl. 8, 79 (1959). 

Carbon tetrachloride (CCL ) was a widely used industrial solvent and cleaner. It produces liver injury in rats and mice that has served as a useful experimental model for certain hepatotoxic effects (Renner 1985 Slater 1981). A single dose of CCLt when administered to a rat produces centrilobular necrosis and fatty degeneration of the Uver, and chronic low dose exposure is associated with liver cirrhosis (Slater et al. 1985). These hepatotoxic effects of CCI4 are mediated through its metabolic activation in the liver by CYP2E1 to reactive intermediates, including the... 

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