Liver necrosis carbon tetrachloride

Yellow phosphorus was the first identified liver toxin. It causes accumulation of lipids in the liver. Several liver toxins such as chloroform, carbon tetrachloride, and bromobenzene have since been identified. I he forms of acute liver toxicity are accumulation of lipids in the liver, hepartxiellular necrosis, iii-trahepatic cholestasis, and a disease state that resembles viral hepatitis. The types of chrome hepatotoxicity are cirrhosis and liver cancer. 

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... 

Slater, T.F. (1968). The inhibitory effects in vitro of phenothia-zines and other drugs on lipid-peroxidation systems in rat liver microsomes, and their relationship to the liver necrosis produced by carbon tetrachloride. Biochem. J. 106, 155-160. 

Danni 0, Aragno M, Ugazio G. 1988. In vivo studies on halogen compound interactions. I. Effects of carbon tetrachloride plus 1,2-dibromoethane on liver necrosis. Res Commun Chem Pathol Pharmacol 61 377-390. 

A number of animal studies suggest that hepatomas occur only after liver necrosis and fibrosis have occurred and, therefore, that carbon tetrachloride is not a direct liver carcinogen." One early study, however, found that liver necrosis and its associated chronic regenerative state probably were not necessary for tumor induction, although a correlation was found between the degree of liver necrosis and the incidence of hepatomas. "... 

Hepatic Effects. Carbon tetrachloride has been known for many years to be a powerful hepatotoxic agent in humans and in animals. The principal clinical signs of liver injury in humans who inhale carbon tetrachloride are a swollen and tender liver, elevated levels of hepatic enzyme (aspartate aminotransferase) in the serum, elevated serum bilirubin levels and the appearance of jaundice, and decreased serum levels of proteins such as albumin and fibrinogen (Ashe and Sailer 1942 McGuire 1932 New et al. 1962 Norwood et al. 1950 Straus 1954). In cases of acute lethal exposures, autopsy generally reveals marked liver necrosis with pronounced steatosis (Jennings 1955 Markham 1967 Smetana 1939), and repeated or chronic exposures leads in some cases to fibrosis or cirrhosis (McDermott and Hardy 1963). 

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). 

Haloalkanes. Certain haloalkanes and haloalkane-containing mixtures have been demonstrated to potentiate carbon tetrachloride hepatotoxicity. Pretreatment of rats with trichloroethylene (TCE) enhanced carbon tetrachloride-induced hepatotoxicity, and a mixture of nontoxic doses of TCE and carbon tetrachloride elicited moderate to severe liver injury (Pessayre et al. 1982). The researchers believed that the interaction was mediated by TCE itself rather than its metabolites. TCE can also potentiate hepatic damage produced by low (10 ppm) concentrations of carbon tetrachloride in ethanol pretreated rats (Ikatsu and Nakajima 1992). Acetone was a more potent potentiator of carbon tetrachloride hepatotoxicity than was TCE, and acetone pretreatment also enhanced the hepatotoxic response of rats to a TCE-carbon tetrachloride mixture (Charbonneau et al. 1986). The potentiating action of acetone may involve not only increased metabolic activation of TCE and/or carbon tetrachloride, but also possible alteration of the integrity of organelle membranes. Carbon tetrachloride-induced liver necrosis and lipid peroxidation in the rat has been reported to be potentiated by 1,2- dichloroethane in an interaction that does not involve depletion of reduced liver glutathione, and that is prevented by vitamin E (Aragno et al. 1992). 

Aragno M, Tamagno E, Danni O, et al. 1992. In wVo studies on halogen compound interactions. III. Effect of carbon tetrachloride plus 1,2- dichloroethane on liver necrosis and fatty accumulation. Research Communication in Chemical Pathology and Pharmacology 76 341-354. 

Bernacchi AS, Fernandez G, Villarruel MC, et al. 1988. Further studies on the late preventive effects of the anticalmodulin trifluoperazine on carbon tetrachloride-induced liver necrosis. Exp Mol Pathol 48 286-300. 

De Toranzo EG, Diaz Gomez Ml, Castro JA. 1978a. Carbon tetrachloride activation, lipid peroxidation and liver necrosis in different strains of mice. Res Common Chem Pathol Pharmacol 19 347- 352. 

Eschenbrenner AB, Miller E. 1946. Liver necrosis and the induction of carbon tetrachloride hepatomas in strain A mice. J Natl Cancer Inst 6 325- 341. 

The hepatocytes, or parenchymal cells, represent about 80% of the liver by volume and are the major source of metabolic activity. However, this metabolic activity varies depending on the location of the hepatocyte. Thus, zone 1 hepatocytes are more aerobic and therefore are particularly equipped for pathways such as the p-oxidation of fats, and they also have more GSH and GSH peroxidase. These hepatocytes also contain alcohol dehydrogenase and are able to metabolize allyl alcohol to the toxic metabolite acrolein, which causes necrosis in zone 1. Conversely, zone 3 hepatocytes have a higher level of cytochromes P-450 and NADPH cytochrome P-450 reductase, and lipid synthesis is higher in this area. This may explain why zone 3 is most often damaged, and lipid accumulation is a common response (see "Carbon Tetrachloride," for instance, chap. 7). 

This is the accumulation of triglycerides in hepatocytes, and there are a number of mechanisms underlying this response as is discussed below (see the sect. "Mechanisms of Toxicity"). The liver has an important role in lipid metabolism, and triglyceride synthesis occurs particularly in zone 3. Consequently, fatty liver is a common response to toxicity, often the result of interference with protein synthesis, and may be the only response as after exposure to hydrazine, ethionine, and tetracycline, or it may occur in combination with necrosis as with carbon tetrachloride. It is normally a reversible response, which does not usually lead to cell death, although it can be very serious as is the case with tetracycline-induced fatty liver in humans. Repeated exposure to compounds, which cause fatty liver, such as alcohol, may lead to cirrhosis. 

This is a chronic lesion resulting from repeated injury and subsequent repair. It may result from either hepatocyte damage or cholestatic damage, each giving rise to a different kind of cirrhosis. Thus, carbon tetrachloride will cause liver cirrhosis after repeated exposure, but also compounds, which do not cause acute necrosis, such as ethionine and alcohol may cause cirrhosis after chronic exposure. 

TISSUE LESIONS LIVER NECROSIS 7.2.1 Carbon Tetrachloride... 

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... 

Carbon tetrachloride is a hepato toxic solvent, which causes centrilobular necrosis and fatty liver, liver cirrhosis, and tumors and kidney damage after chronic exposure. It is metabolized... 

Carbon tetrachloride causes centrilobular liver necrosis and steatosis after acute exposure, and liver cirrhosis, liver tumors, and kidney damage after chronic administration. The mechanism underlying the acute toxicity to the liver involves metabolic activation by cytochrome P-450 to yield a free radical (trichloromethyl free radical). This reacts with unsaturated fatty acids in the membranes of organelles and leads to toxic products of lipid peroxidation including malondialdehyde and hydroxynonenal. This results in hepatocyte necrosis and inhibition of various metabolic processes including protein synthesis. The latter leads to steatosis as a result of inhibition of the synthesis of lipoproteins required for triglyceride export. 

Czaja, M.J., Xu, J. Alt, E. (1995) Prevention of carbon tetrachloride-induced rat liver injury by soluble tumor necrosis factor receptor. Gastroenterology, 108. 1849-1854... 

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