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)

The first clinical studies on hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors reported a low incidence of liver toxicity. The personal observation of a case of simvastatin-induced acute cholestatic hepatitis prompted us to evaluate the true incidence of hepatic side effects of these drugs in a large Italian population. One hundred patients taking simvastatin and ninety patients treated with pravastatin were followed-up six months with periodical evaluation of serum lipid levels and liver function test. In 5% of simvastatin-treated patients and 4.5% of pravastatin-treated patients significant liver toxicity was observed, which required drug discontinuation. The mechanism of liver damage was direct, idiosyncratic, but immunological features of drug toxicity could be hypothesized in one patient.
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PMID:Hepatotoxicity of hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors. 152 Jul 52

Nitrofurantoin is a widely utilized urinary antimicrobial drug which has been associated with pulmonary fibrosis, neuropathy, and hepatitis as well as hemolytic anemia in glucose-6-phosphate dehydrogenase-deficient individuals. Incubation of freshly isolated rat hepatocytes with nitrofurantoin caused oxygen activation as a result of futile redox cycling. Glutathione disulfide (GSSG) was formed and rapidly exported from the cell resulting in complete glutathione (GSH) depletion followed by cell death. However, fructose prevented the export of GSSG from the cell and GSH levels recovered rapidly without cytotoxicity occurring. Fructose did not affect nitrofurantoin metabolism but rapidly depleted cellular ATP levels by approximately 80% which remained depressed during the incubation period. Fructose, however, did not protect hepatocytes from nitrofurantoin-induced cytotoxicity if GSH was depleted beforehand. Protection by fructose only occurred at concentrations which caused ATP depletion. These results suggest that fructose prevents nitrofurantoin-induced toxicity by depleting ATP and thereby preventing the ATP-dependent GSSG efflux. GSSG is retained enabling NADPH and glutathione-reductase to reduce the GSSG back to GSH, thereby protecting the cell from nitrofurantoin-induced oxidative stress.
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PMID:Prevention of nitrofurantoin-induced cytotoxicity in isolated hepatocytes by fructose. 189 74

The metabolism of chemical carcinogens was investigated in liver preparations from 28 captive woodchucks (Marmota monax). Of these, 23 were naturally infected with the woodchuck hepatitis virus (WHV), and eight also had primary hepatocellular carcinoma (PHC). Twenty-nine parameters were investigated in liver subcellular fractions, including cross-reactivity with HBsAg, and biochemical parameters, such as gamma-glutamyl transpeptidase, cytochrome P-450 and microsomal monooxygenases (aryl hydrocarbon hydroxylase, ethoxycoumarin and ethoxyresorufin deethylases, aminopyrine and dimethylnitrosamine demethylases, and testosterone 7 alpha-, 16 alpha- and 6 beta-hydroxylases), uridine 5'-diphosphoglucuronosyl transferase, GSH and related enzymes (peroxidase, reductase and S-transferase), as well as other cytosolic enzyme activities (glucose 6-phosphate and 6-phosphogluconate dehydrogenases, NADPH- and NADH-dependent diaphorases, and DT diaphorase). In addition, liver preparations were used in order to quantify the metabolic activation into bacterial mutagens of five procarcinogens (aflatoxin B1, the pyrolysis products Trp-P-2 and MeIQ, 2-aminofluorene and dimethylnitrosamine) and the decrease of potency of three direct-acting mutagens (sodium dichromate, ICR 191 and 4-nitroquinoline 1-oxide). WHV infection produced a significant stimulation of carcinogen metabolism, as shown by the simultaneous change in detoxification parameters (GSH depletion) and activation indices (enhancement of microsomal monooxygenases and of procarcinogen activation into mutagenic metabolites). There were no significant differences between WHV-positive samples from animals without PHC and the noncancerous tissue of PHC-bearing animals, whereas a decrease of both activation and detoxification indices was recorded in the tumorous tissue. There was a considerable interindividual variability among WHV carriers, which was tentatively ascribed to genetic factors. Pregnancy was the only known factor influencing the results in WHV carriers. However, even by excluding pregnant animals, the effects on carcinogen metabolism produced by WHV infection were still statistically significant. These results, together with previous data obtained in humans, revealed that metabolic factors may play a role in the synergism between viral hepatitis and chemical hepatocarcinogens in the etiopathogenesis of PHC.
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PMID:Enhanced metabolic activation of chemical hepatocarcinogens in woodchucks infected with hepatitis B virus. 272 Sep 3

The toxicities of antimalarial drugs vary because of the differences in the chemical structures of these compounds. Quinine, the oldest antimalarial, has been used for 300 years. Of the 200 to 300 compounds synthesised since the first synthetic antimalarial, primaquine in 1926, 15 to 20 are currently used for malaria treatment, most of which are quinoline derivatives. Quinoline derivatives, particularly quinine and chloroquine, are highly toxic in overdose. The toxic effects are related to their quinidine-like actions on the heart and include circulatory arrest, cardiogenic shock, conduction disturbances and ventricular arrhythmias. Additional clinical features are obnubilation, coma, convulsions, respiratory depression. Blindness is a frequent complication in quinine overdose. Hypokalaemia is consistently present, although apparently self-correcting, in severe chloroquine poisoning and is a good index of severity. Recent toxicokinetic studies of quinine and chloroquine showed good correlations between dose ingested, serum concentrations and clinical features, and confirmed the inefficacy of haemodialysis, haemoperfusion and peritoneal dialysis for enhancing drug removal. The other quinoline derivatives appear to be less toxic. Amodiaquine may induce side effects such as gastrointestinal symptoms, agranulocytosis and hepatitis. The main feature of primaquine overdose is methaemoglobinaemia. No cases of mefloquine and piperaquine overdose have been reported. Overdose with quinacrine, an acridine derivative, may result in nausea, vomiting, confusion, convulsion and acute psychosis. The dehydrofolate reductase inhibitors used in malaria treatment are sulfadoxine, dapsone, proguanil (chloroguanide), trimethoprim and pyrimethamine. Most of these drugs are given in combination. Proguanil is one of the safest antimalarials. Convulsion, coma and blindness have been reported in pyrimethamine overdose. Sulfadoxine can induce Lyell and Stevens-Johnson syndromes. The main feature of dapsone poisoning is severe methaemoglobinaemia which is related to dapsone and to its metabolites. Recent toxicokinetic studies confirmed the efficacy of oral activated charcoal, haemodialysis and haemoperfusion in enhancing removal of dapsone and its metabolites. No overdose has been reported with artemesinine, a new antimalarial tested in the People's Republic of China. The general management of antimalarial overdose include gastric lavage and symptomatic treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Clinical features and management of poisoning due to antimalarial drugs. 330 66

The Long-Evans Cinnamon rat is a mutant strain that contracts hereditary hepatitis and, eventually, spontaneous hepatoma. Recently, abnormal copper accumulations in Long-Evans Cinnamon rat livers were shown to be genetically linked to the development of hepatitis. Because reduced glutathione and glutathione-related enzymes are known to play important roles in cellular resistance to transition metal toxicity, we determined the levels of reduced glutathione and glutathione-related enzymes in seven different tissues of Long-Evans Cinnamon and control Long-Evans Agouti rats. Of the enzymes examined, only hepatic glutathione peroxidase was markedly decreased in Long-Evans Cinnamon rats. Glutathione peroxidase content in the liver of Long-Evans Cinnamon rats was 39%, 53% and 58% of the control values at 9 (normal stage), 19 (acute hepatitis stage) and 27 (chronic hepatitis stage) wk of age, respectively. Northern-blot analysis revealed that messenger RNA levels of glutathione peroxidase in the livers of Long-Evans Cinnamon rats were about 40% of the control levels. The activity of glutathione S-transferase was slightly decreased in the livers of Long-Evans Cinnamon rats. These data suggest that the liver of the Long-Evans Cinnamon rat is poorly protected against active oxygen species, the production of which is enhanced in the presence of excess copper. Glutathione-reductase activity in the livers of Long-Evans Cinnamon rats increased to 166% and 148% of the control levels at 19 and 27 wk of age, respectively. No significant changes were observed in the activity of gamma-glutamylcysteine synthetase or in the content of total reduced glutathione in the liver of the Long-Evans Cinnamon rat.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decreased expression of liver glutathione peroxidase in Long-Evans cinnamon mutant rats predisposed to hepatitis and hepatoma. 811 95

We attempted to produce a model mouse with a liver injury resulting from an immunological mechanism in C57BL/6J mice, and the effect of hepatitis on the hepatic microsomal mixed-function oxidase system was studied. An experimental immunological liver injury model was caused by the intravenous injection of an anti-basic liver protein (BLP) antibody in mice which had been previously immunized with normal rabbit IgG (RGG) and complete Freund's adjuvant. C57BL/6J strain mice showed the highest susceptibility to the immunological liver injury. Typical histopathological changes in the liver included submassive hepatocellular necrosis and infiltration of lymphocytes into the portal tract and sinusoid area in a necrotic lesion. The liver injury in this model was markedly inhibited by the administration of prednisolone (20 mg/kg, p.o.), cyclophosphamide (15 mg/kg, i.p.), levamisole (10 mg/kg, p.o.), glycyrrhizin (50 mg/kg, i.p.) and cepharanthine (10 mg/kg, i.p.), which act on the immune system. Twenty-four hours after the injection of anti-BLP antibody, the activities of aminopyrine N-demethylase, aniline hydroxylase and NADPH-cytochrome c reductase and the content of cytochrome P-450 were mostly reduced, whereas cytochrome b5 and NADH-ferricyanide reductase were not. These results suggest that the experimental liver injury model in C57BL/6J mice is useful as a model of liver injury model, and its hepatitis was shown to inhibit the cytochrome P-450-dependent biotransformation of drugs in the mouse.
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PMID:Effect of anti-basic liver protein antibody-induced liver injury on hepatic drug-metabolizing enzymes in C57 BL/6J mice. 828 50

Dyslipidaemia may be treated with a number of safe and effective pharmacological agents that target specific lipid disorders through a variety of mechanisms. The bile-acid sequestrants--cholestyramine and colestipol--primarily decrease LDL cholesterol by binding bile acids, thereby decreasing intrahepatic cholesterol, and by increasing the activity of LDL receptors. Nicotinic acid lowers LDL cholesterol and triglyceride by decreasing VLDL synthesis and by decreasing free fatty acid mobilization from peripheral adipocytes. The HMG-CoA reductase inhibitors--fluvastatin, lovastatin, pravastatin and simvastatin--lower LDL cholesterol by partially inhibiting HMG-CoA reductase (the rate-limiting enzyme of cholesterol biosynthesis) and by increasing the activity of LDL receptors. The fibric-acid derivatives--bezafibrate, ciprofibrate, clofibrate, fenofibrate and gemfibrozil--primarily decrease triglyceride by increasing lipoprotein lipase activity and by decreasing the release of free fatty acids from peripheral adipose tissue. Probucol decreases LDL cholesterol by increasing non-receptor-mediated LDL clearance; as an anti-oxidant, probucol also decreases LDL oxidation; oxidized LDL which is thought to lead to atherogenesis. Although these agents have been proven safe in clinical trials, like any drug, they carry the risk for adverse effects. The bile-acid sequestrants may cause constipation, reflux oesophagitis, and dyspepsia, and may bind coadministered medications such as digitalis glycosides, beta blockers, warfarin, and exogenous thyroid hormone. Nicotinic acid use is commonly associated with flushing and pruritus and may also cause non-specific gastrointestinal complaints, hepatotoxicity (hepatic necrosis, hepatitis, or elevated liver enzymes), gout, myolysis, decreased glucose tolerance and increased fasting glucose levels, and ophthalmological complications including decreased visual acuity, toxic amblyopia, and cystic maculopathy. The HMG-CoA reductase inhibitors may produce liver enzyme elevations, creatine kinase elevations and rhabdomyolysis. The combination of a reductase inhibitor and a fibrate increases the risk for rhabdomyolysis. Possible adverse effects of the fibric-acid derivatives include abdominal discomfort, nausea, flatulence, increased lithogenicity of bile, liver enzyme elevations and creatine kinase elevations. Probucol may increase the QTc interval and may cause non-specific gastrointestinal complaints.
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PMID:Currently available hypolipidaemic drugs and future therapeutic developments. 859 27

Niacin has been used for many years to treat hyperlipidemia. It has been shown to reduce coronary death and non-fatal myocardial infarction and, in a separate analysis of long-term (15-year) follow-up, all cause mortality. It reduces total cholesterol, low density lipoprotein cholesterol (LDL-C) and triglycerides and increases high density lipoprotein cholesterol (HDL-C). Sustained-release niacin may be associated with more dramatic changes in LDL-C and triglyceride, whereas the short acting preparation causes greater increases in HDL-C. The increase of HDL-C occurs at a lower dose (1500 mg/day) than the reduction of LDL-C (> 1500 mg/day). Niacin also favorably influences other lipid parameters including lipoprotein(a) [Lp(a)], alimentary lipemia, familial defective apolipoprotein B-100 and small dense LDL. Combination of niacin with a bile acid sequestrant or a reductase inhibitor represents a powerful lipid-altering regimen. Whereas the reductase inhibitors and bile acid binding resins primarily affect LDL-C, the combined therapy has a synergistic effect to reduce LDL-C and, in addition, the niacin reduces triglycerides and increases HDL-C. The major drawback in the use of niacin is associated side effects (flushing and palpitations) and toxicity (worsening of diabetes control, exacerbation of peptic ulcer disease, gout, hepatitis). Niacin has a long history of use as a lipid lowering agent and has several attractive features. Unfortunately, the side effect profile of this agent warrants its use only in patients with marked dyslipidemia in whom side effects and potential toxicity are closely monitored.
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PMID:New developments in the use of niacin for treatment of hyperlipidemia: new considerations in the use of an old drug. 885 85

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

To confirm whether or not cytosolic NADPH-UQ reductase is involved in the recycling of cellular ubiquinol (UQH2) consumed during lipid peroxidation, the effect of a UQ-10 supplement on the NADPH-UQ reductase and cellular defense against oxidative damage in rat livers was investigated. Supplements of UQ-10 for 14 days enhanced the levels of UQH2-10 and NADPH-UQ reductase in rat livers without any appreciable changes in other antioxidant contents and related enzyme activities. However, the injection of carbon tetrachloride (CCl4) into the rats induced lipid peroxidation and decreased the cellular UQH2-10 contents (and increased equivalent amounts of UQ-10), as well as decreasing the ascorbic acid, reduced glutathione (GSH) and alpha-tocopherol contents of the rat livers. Administration of the UQ-10 supplement prior to the CCl4 treatment spared alpha-tocopherol (but not GSH or ascorbic acid), inhibited lipid peroxidation, and thus improved CCl4-induced hepatitis. These findings support the notion that NADPH-UQ reductase in cytosol is the enzyme responsible for the regeneration of UQH2 from UQ formed by lipid peroxidation in cells.
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PMID:Cytosolic NADPH-UQ reductase-linked recycling of cellular ubiquinol: its protective effect against carbon tetrachloride hepatotoxicity in rat. 926 8


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