Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gentiopicroside (GPS), a main bitter secoiridoid constituent of roots of Gentiana macrophylla Pall., was tested for therapeutic effects on the two hepatic injury models, the CCl4-induced and lipopolysaccharide (LPS)/bacillus Calmette-Guerin (BCG)-induced hepatitides. An increase in serum level of hepatic aminotransferases (GOT: EC 2.6.1.1. and GPT: EC 2.6.1.2.) induced by a p.o. treatment of CCl4 was suppressed by pretreatment with GPS at 30-60 mg/kg/day for 5 consecutive days. An increase of these enzymes triggered by an i.v. treatment with LPS in mice primed with bacillus Calmette-Guerin (BCG) was also inhibited by GPS pretreatment at the same dose of GPS. In the BCG/LPS model, tumor necrosis factor (TNF), a major inflammatory mediator, was increased in serum with a peak at 90-120 min, followed by an increase of serum transaminase activities. GPS treatment significantly suppressed the increase of TNF in serum at the therapeutic doses, suggesting that GPS protected against hepatitis by inhibiting the production of TNF.
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PMID:Suppression of chemically and immunologically induced hepatic injuries by gentiopicroside in mice. 799 67

This review focuses on cellular events that modulate hepatotoxicity subsequent to initial liver insult. Cellular events that determine the nature and extent of hepatotoxic injury and the ultimate outcome of that injury are also discussed. The roles of cell types other than hepatocytes, hepatocyte organelle-specific processes, and regeneration in progression or recovery from liver injury are emphasized. Leukocyte activities are key events in two distinct hepatotoxicities. Neutrophil-mediated, periportal inflammation appears to play a primary role in progression of alpha-naphthylisothiocyanate-induced cholangiolitic hepatitis. However, a humorally mediated autoimmune response to protein adducts that occurs after anesthesia is critical in onset of halothane-induced hepatitis. New insights into specific events at the hepatocyte level are also emerging. Although reducing gap junctional communication between hepatocytes can protect against progression of liver injury, down-regulation of the subunit proteins (connexins) can isolate neoplastic cells from growth regulation. Acidic intracellular pH characteristic of hypoxia is protective against both hypoxic and toxicant-induced cell injury. In oxidative injury, a pH-mediated mitochondrial permeability transition causes mitochondrial uncoupling and ATP loss and leads to cell death. The ultimate outcome of hepatotoxic injury depends on the extent of tissue repair. Stimulation of tissue repair after a sublethal dose of CCl4 appears to be the central mechanism in protection against death from a subsequent large dose. Taken together, these examples illustrate the importance of events subsequent to initial liver injury as determinants of extent of liver damage.
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PMID:Novel mechanisms in chemically induced hepatotoxicity. 800 41

Carbon tetrachloride induces diffuse fatty degeneration and centrilobular necrosis in the liver and the severity of liver injury is roughly proportional to the dosage administered. Nonetheless, the incidence of cirrhosis by this agent is rare. Several drugs, including methyldopa, methotrexate, isoniazid and vitamin A, have occasionally been reported to cause chronic active hepatitis, fibrosis and cirrhosis. There is no question that continued administration of the drug in the presence of clinically apparent hepatitis can lead to chronic active hepatitis, fibrosis and cirrhosis. Early recognition that a therapeutic drug is the probable cause of liver injury, followed by prompt withdrawal of such a drug, generally suffices in the management of drug-induced chronic liver disease.
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PMID:[Toxic cirrhosis]. 811 7

Content of cytochromes P-450 and b5 and the rate of oxidative dealkylation in liver microsomes as well as the antipyrine pharmacokinetics were normalized in rats with acute CCl4-induced hepatitis after treatment with cordiamine (diethyl nicotinamide) at a dose of 40 mg, subcutaneously, 2 times daily within 4 days. Cordiamine (30 drops 3 times daily within 8 days) contributed to normalization of the hydroxylating reaction in liver tissue of patients with viral hepatitis A, estimated by the "antipyrine" test. The drug exhibited stabilizing effect on hydrophobic interactions in microsomal membranes; diethyl nicotinamide possessed antiradical and vitamin properties.
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PMID:[Correction of disorders in the monooxygenase system function with diethylnicotinamide (cordiamine) in tetrachloromethane- induced and viral hepatitis]. 827 44

Liver accumulation of 99mTc-DL-homocysteine (99mTc-Hcy), which had been found to accumulate in several experimental tumors, was studied using experimental hepatitis models of rats. The distribution of this compound in liver of rats treated with CCl4 (25-100 microL/100 g body weight) was more than five times higher than that of non-treated rats, corresponding to the accumulation of Evans Blue, a marker dye for capillary permeability. Furthermore, in vitro experiments indicated that the liver accumulation of 99mTc-Hcy was due to some changes in the plasma membranes caused by CCl4 administration. These results indicate that lesional accumulation of 99mTc-Hcy is due to, at least in part, an enlarged capillary permeability similar to the case of malignant tissues reported previously.
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PMID:Liver distribution of 99mTc-DL-homocysteine in experimental hepatitis rats. 829 70

In chronic hepatitis induced by long-term CCl4 administration to rats, there was largely an increase in the formation of malonic dialdehyde and Schiff bases, an elevation of glycosaminoglycans and hydroxyproline in collagen fractions, and proliferation of hepatic fibrous tissue. Therapy of CCl4-induced hepatitis with the hepatoprotective antioxidants essentiale and legalone led to decreases in the rate of lipid peroxidation, the production of glycosaminoglycans and collagen and to morphological manifestations of hepatic fibrosis. There was a moderate correlation between the indices of lipid peroxidation and hepatic fibrosis.
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PMID:[Role of lipid peroxidation in the mechanism of proliferation of hepatic fibrous tissue in experimental chronic hepatitis]. 875 46

The hepatoprotective effect of Alstonia scholaris R. Br. on liver injuries induced by carbon tetrachloride (CCl4). beta-D-galactosamine, acetaminophen and ethanol were investigated by means of serum-biochemical and histopathological examinations. Post treatment of A scholaris reduced dose-dependently the elevation of serum transaminases level and histopathological changes such as cell necrosis, inflammatory cell infiltration, which were caused by the single administration of 32 microliters/kg CCl4 or 600 mg/kg acetaminophen in mice. A. scholaris significantly lowered 288 mg/kg beta-D-galactosamine induced serum transaminases elevation in the serum-biochemical analysis in rats. A tendency was also shown to inhibit cell necrosis and inflammatory cell infiltration caused by beta-D-galactosamine in histopathological examination. All serological and histopathological effects of A. scholaris were compared with those of Bupleurum chinense, which has been reported previously as a treatment criteria of hepatitis.
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PMID:The protective effect of Alstonia scholaris R. Br. on hepatotoxin-induced acute liver damage. 887 72

We found that NADPH-dependent ubiquinone reductase (NADPH-UQ reductase) in rat liver cytosol reduces ubiquinone (UQ) to ubiquinol (UQH2) in lipid membranes and consequently inhibits lipid peroxidation [Takahashi T., et al., Biochem. J., 309, 883-890 (1995)]. Here we examined whether or not this UQH2-regenerating system functions as a cellular antioxidant defense in animals. Rats were given UQ-10 for 2 weeks, and were then exposed to carbon tetrachloride (CCl4). The UQ-10 supplement increased only in the NADPH-UQ reductase and the UQH2-10 pool of rat liver without any appreciable change in the levels of other antioxidant factors. On the other hand, CCl4 markedly increased plasma aspartate aminotransferase and alanine aminotransferase, liver weight and thiobarbituric acid reacting substances formation, which are indicators of CCl4-hepatitis, and it decreased the liver levels of L-ascorbic acid, reduced form of glutathione (GSH), alpha-tocopherol, NADPH-UQ reductase and glutathione S-transferase. However, all the above indicators of CCl4-induced hepatitis were significantly improved in rats given UQ-10. Furthermore, alpha-tocopherol, but neither L-ascorbic acid nor GSH, was significantly saved. UQ-10 supplement also was recovered glutathione S-transferase and NADPH-UQ reductase activities slightly. These results indicated that UQ-10 given to rats increased the cellular UQH2-10 pool and cytosolic NADPH-UQ reductase activity in their livers, resulting in the inhibition of lipid peroxidation in the biomembranes, and consequently protected the rats from the CCl4-hepatotoxicity.
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PMID:Cellular antioxidant defense by a ubiquinol-regenerating system coupled with cytosolic NADPH-dependent ubiquinone reductase: protective effect against carbon tetrachloride-induced hepatotoxicity in the rat. 887 5

Fatigue is a common complaint in patients with liver disease; however, the etiology of fatigue is poorly understood and no therapeutic options are available to treat it. Altered central neurotransmission, especially serotonergic, appears to play a role in the genesis of fatigue. In this study, we describe a rat model of fatigue assessment using a swim tank, and we used this model to document the degree of fatigue in rat models of cholestasis caused by bile duct resection (BDR) and of hepatitis caused by carbon tetrachloride (CCl4) administration. Fatigue was quantitated as the time spent floating and struggling over a 15-minute period after placement in the swim tank, and an overall activity score was calculated. Using this technique, BDR rats exhibited significantly enhanced floating times and an overall reduction in activity score compared with noncholestatic controls (P < or = .01). On the other hand, CCl4-treated rats showed a marked variability in floating and struggling times and activity scores such that, overall, CCl4-treated rats were not significantly different from normal controls. Therefore, we used BDR and noncholestatic control rats to examine the effects of a serotonin (5HT1A) receptor agonist (LY293284) on cholestasis-associated fatigue. BDR rats treated with LY293284 (0.3 mg/kg subcutaneously 24, 5, and 1 hour before placement in the swim tank) showed marked reductions in floating times and an increase in overall activity scores compared with BDR controls (P < or = .001). LY293284 was without effect in noncholestatic animals. These results suggest that fatigue can be quantitated in rat models of liver disease and that 5HT1A receptor agonists may provide a useful therapeutic tool in the treatment of cholestatic liver disease-associated fatigue.
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PMID:Improvement in cholestasis-associated fatigue with a serotonin receptor agonist using a novel rat model of fatigue assessment. 902 69

Despite good evidence for p53 dysfunction in human hepatocellular carcinomas, little is known of the significance of p53 to normal hepatocytes and whether p53 dysfunction is relevant to early hepatocarcinogenesis. We have therefore examined the consequences of targeted p53 deficiency in hepatocytes for regulation of apoptosis, proliferation, and ploidy. p53 deficiency was silent in normal liver and did not affect progression from diploidy to polyploidy in the aging liver. However, in primary culture the absence of p53 resulted in increased hepatocyte proliferation indices and decreased sensitivity to proliferation inhibition by TGFbeta. Moreover, p53-deficient cells continued to survive and proliferate under conditions of minimal trophic support that led to growth arrest and apoptosis of wild-type cells. In vivo, p53-deficient mice had enhanced proliferative responses to both xenobiotic hepatomitogen and CCl4-induced liver necrosis, although lack of persistent proliferation showed that other control mechanisms are important. There was no simple relationship between p53 and apoptosis after DNA damage because UV irradiation led to p53-independent apoptosis, even though p53 was stabilized. However, p53 did couple DNA damage to growth arrest, and abnormal mitoses after gamma-irradiation of regenerating p53 null livers demonstrated circumstances where loss of G1 and G2 checkpoints may generate abnormal ploidy. Thus p53 becomes important when hepatocytes are released from G0 and stressed, sensitizing them to mitogen and cytokine regulators of cell cycle progression and apoptosis. Hence p53 deficiency is likely to be significant in an environment of persistent regenerative stimuli and unfavorable trophic support or in the presence of other enabling genetic lesions. This model is relevant to human hepatocarcinogenesis, which almost always occurs against a background of chronic hepatocellular destruction in hepatitis and cirrhosis. In that context, by reducing the need for cytokine support and disabling DNA damage-induced growth arrest, p53 deficiency should facilitate the expansion of preneoplastic clones in chronic liver disease.
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PMID:p53 Deficiency in liver reduces local control of survival and proliferation, but does not affect apoptosis after DNA damage. 921 83


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