Liver necrosis

As regards toxicity, pyrazole itself induced hyperplasia of the thyroid, hepatomegaly, atrophy of the testis, anemia and bone marrow depression in rats and mice (72E1198). The 4-methyl derivative is well tolerated and may be more useful than pyrazole for pharmacological and metabolic studies of inhibition of ethanol metabolism. It has been shown (79MI40404) that administration of pyrazole or ethanol to rats had only moderate effects on the liver, but combined treatment resulted in severe hepatotoxic effects with liver necrosis. The fact that pyrazole strongly intensified the toxic effects of ethanol is due to inhibition of the enzymes involved in alcohol oxidation (Section 4.04.4.1.1). 

Attention has been called recently to Amsinckia intermedia as causing liver necrosis in swine, horses and cattle. Like Heliotropium and Tri-chodesma, it belongs to the Boraginacese. ... 

The purpose of this study was to compare hepatotoxic effects of monobromo-benzene, 3 dibromobenzene isomers, hexabromobenzene and tetrabromobisphenol A with special attention paid to the dynamics of changes of selected indicators of liver necrosis during acute poisoning. 

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. 

No changes in GTP and y-GT activity were recorded after repeated administration of the above compounds. Also, histopathological examination did not point to liver necrosis. Similar phenomenon detected earlier after repeated administration of monobromobenzene, was interpreted as a result of damage of the microsomal enzymatic system responsible for the appearance of active metabolites (ref. 22). 

Tucker et al. 1982). Increasing severity of liver necrosis with dose was also seen in the studies by Buben and O Flaherty (1985) and Stott et al. (1982). 

French, S.W., Benson, N.C. and Sun, P.S. (1984). Cen-trilobular liver necrosis induced by hypoxia in chronic ethanol-fed rats. Hepatology 4, 912-917. 

Tsukamoto, H., Gaal, K. and French, S.W. (1990). Insights into the pathogenesis of alcoholic liver necrosis and fibrosis, status report. Hepatology 12, 599-608. 

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. 

Vital Signs. Although hypertension is common and may be severe, hypotension can also occur. Tachycardia occurs in about 30 percent of cases. Severe tachypnea with respiratory rates as high as 88/min or respiratory depression with rates of 10/min or less may be seen. Respiratory arrest and cardiac arrest may occur. Hyperthermia with temperatures as high as 108.0 °F is a life-threatening event and may be associated with submassive liver necrosis (Armen et al. 1984). 

Armen, R. Kanel, G. and Reynolds, T. Phencyclidine-induced malignant hyperthermia causing submassive liver necrosis. Am J Med 77 167-172, 1984. 

The low concentration group appeared normal at 1000 gg/L, pulmonary inflammation and liver necrosis at high concentration, all had nonspecific inflammation of brain, heart, lung, liver, and kidney... 

Increased liver to BW ratios in both sexes. At higher dietary concentrations equivalent to 0.43 and 1.1 mg/kg BW daily, liver necrosis was observed in males (USEPA 1988)... 

Fatal chronic selenosis in aquatic birds is characterized by low body weight or emaciation, liver necrosis, enlarged kidneys (up to 40% heavier than normal), and more than 66 mg Se/kg DW liver... 

Nakae, D. et al., Liposome-encapsulated superoxide dismutase prevents liver necrosis induced by acetaminophen, Am. J. Pathol., 136, 787, 1990. 

Brodie, B.B. et al. 1971. Possible mechanism of liver necrosis caused by aromatic organic compounds. Proc. Natl. Acad. Sci. USA 68 160. 

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. 

Extensive metabolic work continues with the pyrrolizidine alkaloids many of which are known toxic principles of plants responsible for conditions such as irreversible hemorrhagic liver necrosis, megalocytosis, and cancer. Considerable interest remains in the metabolism of pyrrolizidine alkaloids and their A-oxides to metabolic pyrroles thought to participate in molecular events associated with the above-mentioned toxicities. The chemistry and pharmacological properties of the pyrrolizidine alkaloids is authoritatively discussed by Wrobel in Volume 26 of this treatise. 

A systematic series of studies on the ECT of pig liver have appeared from the Australian group of Maddern et al. Electrolysis was investigated for generating areas of hepatic necrosis in the pig liver.88 The lesions healed with time and were associated with minimum morbidity. Further work on 21 pigs showed that during ECT of the liver tissue the electrolytic dose (in coulombs cm"3) correlated with the volume of liver necrosis.89 This group also established that in addition to the coulombic dose, pH could be used as a realtime monitor to predict more accurately the extent of necrosis. 

Rabbit 24 hr Hepatic 94 F (centrilobular liver necrosis) Treon et al. 1955... 

The mechanism of toxification of isoniazid was investigated in rats pretreated with inducers or inhibitors of microsomal enzymes or an inhibitor of acylamidases. In animals pretreated with the acylamidase inhibitor bis(4-nitrophenyl) phosphate, isoniazid and acetylisoniazid produced less liver necrosis than in control animals. The treatment had no effect on the necrosis due to acetylhydrazine [173], In animals pretreated with inducers of microsomal cytochrome P450 such as phenobarbital, acetylisoniazid, and acetylhydrazine caused markedly increased necrosis, while pretreatment with cytochrome P450 inhibitors decreased necrosis. In contrast, the toxicity of isoniazid and hydrazine was not modified by phenobarbital pretreatment. From these observations, Trimbell et al. [173] concluded that the hydrolysis of acetylisoniazid is a prerequisite for hepatotoxicity, and that microsomal enzymes transform acetylhydrazine, the product of hydrolysis, to a toxic species. 

Hepatic Effects. Severe liver necrosis occurred in three humans who ingested commercial... 

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. 

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