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 effect of experimental hepatitis, induced by i.p. D-galactosamine, on the metabolism and excretion of [14C]imipramine in the rat is reported. The major consequence was an increase of the conjugated metabolites of imipramine excreted in urine, resulting in a four-fold increase in 2-hydroxyimipramine glucuronide and two-fold increases in 2-hydroxydesmethylimipramine glucuronide and 10-hydroxyimipramine glucuronide. The total excretion of 14C-labelled metabolites in urine of galactosamine-treated rats was 69% dose compared with 37% in untreated animals. Faecal excretion of [14C]imipramine metabolites was lowered from 68% dose in untreated animals to 27% in animals with induced hepatitis. Induction of a galactosamine hepatitis decreased markedly the biliary excretion of imipramine metabolites in bile duct-cannulated rats; 80% dose was excreted in bile in normal rats, and 35.5% in rats with hepatitis. Plasma clearance of imipramine, after i.v. dosage, was decreased by 60% and clearance of metabolites (excluding imipramine) by 40%, in galactosamine hepatitis; the pharmacokinetics changed from a two- to a single-compartment system reflecting decreased extraction and/or metabolism, by the liver. The clinical implications of these findings are discussed in relation to the hazard attending the use of imipramine in patients suffering from liver disease.
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PMID:The metabolism and excretion of [14C]imipramine in an experimental hepatitis. 647 8

D-(+)-galactosamine (GalN) induces severe reversible hepatocellular injury in the rat accompanied by lecithin: cholesterol acyltransferase (LCAT) deficiency, defective chylomicron (CM) catabolism, and accumulation of abnormal plasma lipoproteins (Lps), including discoidal high density lipoproteins (HDL). These abnormalities are presumed to result from hepatic injury alone, but the effect of GalN on intestinal Lps has not been studied. To assess possible effects on intestinal Lp formation and secretion, mesenteric lymph fistula rats were injected with GalN or saline. Twenty-four hours later a 2-hr fasting lymph sample was collected; this was followed by an 8-hr duodenal infusion of a lipid emulsion containing 17.7 mM [3H]triolein at 3 ml/hr. Fasting lymph and fat-infused lymph flow rates, 3H, triglyceride, and cholesterol output, residual 3H in intestinal lumen and mucosa, total 3H recovery, and d less than 1.006 g/ml Lp size and lipid composition were unchanged by GalN treatment, but d less than 1.006 g/ml Lps were depleted of apoE and C. Fat-infused lymph phospholipid (PL) output was higher in GalN rats due to PL-enriched d greater than 1.006 g/ml Lps. Electron microscopy of lymph and plasma LDL and HDL revealed spherical Lps in all samples. GalN plasma, fasting lymph, and fat-infused lymph also contained large abnormal LDL and discoidal HDL. Control lymph LDL and HDL did not differ in size from control plasma LDL and HDL. Control lymph LDL contained both apoB240K and B335K. However, spherical LDL and discoidal HDL in fasting lymph from GalN rats differed significantly in size from the corresponding plasma particles and became closer in size to the plasma particles with fat infusion. GalN lymph LDL contained only apoB240K and had a lower PL/CE than GalN plasma LDL. GalN fasting lymph HDL, depleted of apoC and having a PL/CE of 5, became enriched in apoE and the PL/CE increased to 10 with fat infusion to closely resemble GalN plasma HDL. GalN reduces apoE and C (mainly of hepatic origin) in d less than 1.006 g/ml gut Lps, which may contribute to the CM catabolic defect in GalN rats. Lymph LDL and HDL, especially in fasting lymph, may be partially gut-derived with increased filtration of plasma Lps into lymph with fat infusion. GalN fat-infused lymph HDL is enriched in apoE, but unable to transfer apoE to d less than 1.006 g/ml intestinal Lps. We conclude that GalN hepatitis is a model that allows study of intestinal Lps with normal lipid digestion and absorption in the face of severe hepatic injury and LCAT deficiency.
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PMID:Intestinal lipoproteins in the rat with D-(+)-galactosamine hepatitis. 663 Dec 39

The accelerated transport of the blood neutral amino acids into the brain in encephalopathic patients with fulminant hepatitis and advanced liver cirrhosis was demonstrated not only by determining the cerebrospinal fluid (CSF) aminogram but also by calculating the predicted velocity of the amino acid transport through the blood-brain barrier. Significant elevation in CSF aromatic amino acid (AAA) and methionine levels was observed in the encephalopathic patients. Arousal from hepatic encephalopathy by drip infusion of a branched chain amino acid (BCAA)-enriched solution was obtained coincidentally with the elevated BCAA levels and diminished concentrations of AAA and methionine in CSF. These clinical observations were confirmed experimentally in rats treated with carbon tetrachloride (CCl4) and D-galactosamine by obtaining the elevation of neutral amino acid contents in the brain and the slight increase in the brain uptake index (BUI) of a radiolabeled amino acid.
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PMID:Alterations in neutral amino acid transport across the blood-brain barrier in hepatic failure. 663 35

Studies by Liehr et al. suggest that endotoxins are important in the pathogenesis of galactosamine hepatitis (Gal-N hepatitis) in rats. Lactulose (9.1 gm per kg per day) prevents hepatic lesions induced by Gal-N; an antiendotoxin effect of lactulose is postulated. However, commercial preparations of lactulose are contaminated with galactose, which shows a competitive action to Gal-N. To analyze the effect of galactose, male Wistar rats were pretreated with lactulose (Duphalac, 9.1 gm per kg per day) and given Gal-N (375 mg per kg i.p.). After 24 hr, serum was analyzed for glutamic pyruvate transaminase, glutamate dehydrogenase, and sorbitol dehydrogenase activities. Pretreatment with Duphalac, even 1 hr before Gal-N, abolished toxicity. Duphalac contains 10 gm galactose per 100 ml. Galactose was given in a similar concentration and similar inhibition occurred. Pretreatment with purified lactulose (9.1 gm per kg for 5 days) diminished the effects of Gal-N but did not normalize enzyme concentrations. Because small doses of galactose (80 and 300 mg per kg) showed similar inhibitory effects, we conclude that the protective effect of commercial lactulose preparations is mainly due to galactose contamination and not to an antiendotoxin effect.
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PMID:Galactosamine hepatitis, endotoxemia, and lactulose. 683 15

Chronic ingestion of ethanol (5 g/kg/day) for 6 weeks increased the hepatotoxicity of a single injection of D-galactosamine (330 mg/kg) in rats. Plasma transaminases, alkaline phosphatase, gamma glutamyl transpeptidase and sulphobromophthalein retention were consistently high in alcohol-fed rats compared to sucrose-fed controls, 25 hours after galactosamine administration. Liver histology in sucrose-fed rats revealed typical inflammatory changes and cytoplasmic vacuolation without cell necrosis was seen. Propylthiouracil treatment had no beneficial or protective effect in alcohol-fed rats in this animal model of hepatitis.
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PMID:Potentiation of hepatotoxicity by ethanol in galactosamine-induced hepatitis in rats: role of propylthiouracil protection. 684 26

The effect of the hepatoprotective drug silymarin (Carsil) on the incorporation rate of 14C-leucine into total proteins and on the biosynthesis of UDP-N-acetylhexosamine and microsomal glycoproteins using 14C-glucose of rat liver with D-galactosamine hepatitis was studied. It was found that i.p. treatment with Carsil in a dose of 140 mg/kg applied for 4 consecutive days partly abolishes the inhibitory effect of galactosamine on protein and glycoprotein biosynthesis. The specific activity of 14C-labelled UDP-N-acetylhexosamine is higher in the liver of D-galactosamine treated rats, compared with the specific activity of the nucleotide from liver pretreated with Carsil and then injected with galactosamine. This fact supports the suggestion that Carsil probably activates the metabolic conversion of UDP-hexosamine to the acetylated metabolite-UDP-N-acetylhexosamine, which is the normal liver cell metabolite, in liver cells.
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PMID:Effect of silymarin (Carsil) on the microsomal glycoprotein and protein biosynthesis in liver of rats with experimental galactosamine hepatitis. 688 84

The apoprotein and lipid composition and the morphology of lipoproteins was determined in rats with D-(+)-galactosamine (GalN) hepatitis. Single intraperitoneal injections of GalN at several dose levels and postinjection exsanguination times resulted in depressed levels of cholesteryl esters, an index of plasma lecithin:cholesterol acyltransferase (LCAT) activity, and increased levels of phospholipids, unesterified cholesterol, and triglycerides. Plasma withdrawn from rats 24 hr after injection of 1000 mg/kg GalN was most deficient in cholesteryl ester and was studied further by sequential isolation of VLDL, LDL, HDL1, HDL2, and HDL3. The increased plasma triglyceride (TG) after GalN treatment accumulated in TG-rich VLDL which contained two types of particles: a large (mean diameter 193.6 +/- 48.3 nm) and rough-edged particle, and a smooth one with a mean diameter (63.4 +/- 13.2 nm) similar to control VLDL (69.4 +/- 20.2 nm). The increased phospholiThe increased plasma triglyceride (TG) after GalN treatment accumulated in TG-rich VLDL which contained two types of particles: a large (mean diameter 193.6 +/- 48.3 nm) and rough-edged particle, and a smooth one with a mean diameter (63.4 +/- 13.2 nm) similar to control VLDL (69.4 +/- 20.2 nm). The increased phospholiThe increased plasma triglyceride (TG) after GalN treatment accumulated in TG-rich VLDL which contained two types of particles: a large (mean diameter 193.6 +/- 48.3 nm) and rough-edged particle, and a smooth one with a mean diameter (63.4 +/- 13.2 nm) similar to control VLDL (69.4 +/- 20.2 nm). The increased phospholipids and unesterified cholesterol were predominantly in LDL, HDL1, and HDL2 which were largely rouleaux of flattened vesicles. Density gradient ultracentrifugation of d greater than 1.006 g/ml lipoproteins confirmed these results. GalN hepatitis appeared to decrease the larger apoB335K subspecies and the apoC-III0 and apoC-III2 content of VLDL. However, total apoB concentration as GalN VLDL was increased 2.6-fold over control. LDL and HDL were markedly enriched in apoE. LDL apoB concentration was decreased by 41% while HDL was deficient in apoA-I, A-II and A-IV, and C. These results demonstrate association of increased plasma triglycerides with particles of grossly abnormal apoprotein composition, and the association of increased plasma phospholipids and unesterified cholesterol with apoE-rich lipoproteins during the LCAT defect produced by GalN hepatitis. These abnormal lipoproteins may represent an abnormal level of normal LCAT substrates important in the transport and esterification of plasma cholesterol.
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PMID:Alterations in lipoprotein composition associated with galactosamine-induced rat liver injury. 711 68

1. Following oral administration of [U-14C](+)-catechin to rats with galactosamine-hepatitis, the biliary and faecal elimination of (+)-catechin metabolites was decreased compared with that in normal animals, Renal excretion of (+)-catechin metabolites was enhanced in galactosamine-hepatitis. 2. Although the biliary metabolites were present in similar proportions in galactosamine-hepatitis animals and controls, the major urinary metabolite, 3'-O-methyl (+)-catechin sulphate, was markedly decreased whereas 3'-O-methyl(+)-catechin glucuronide was increased by over 100%. 3. The total overall excretion of 3'-O-methyl (+)-catechin conjugates in rats with galactosamine-hepatitis was similar to that in normal animals indicating that catechol-O-methyltransferase activity is not significantly depressed in galactosamine-hepatitis. 4. Clearance of radioactivity from the blood following i.v. administration of [U-14C]-(+)-catechin was prolonged in galactosamine-hepatitis. 5. Liver perfusion experiments demonstrated depressed glucuronylation of (+)-catechin metabolites in galactosamine-hepatitis, whereas in liver homogenates synthesis of glucuronide conjugates of (+)-catechin metabolites was enhanced. 6. Lung slices were able to metabolize (+)-catechin and the lung is proposed as an extrahepatic site of (+)-catechin metabolism of increased importance in galactosamine-hepatitis. 7. The effects of galactosamine-hepatitis upon the structure of the hepatocyte plasma membrane are discussed in relation to decreased biliary excretion and glucuronylation.
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PMID:Metabolism and excretion of the liver-protective agent (+)-catechin in experimental hepatitis. 714 91

We studied the effects of acute and chronic ethanol feeding on hepatic regeneration in rats following partial hepatectomy and toxic liver injury produced by D-galactosamine. Ethanol, when administered as a single dose (6 gm/kg), inhibited 3H-thymidine incorporation into hepatic DNA; this effect depended in part on the time of ethanol feeding following partial hepatectomy. Multiple ethanol feedings produced an even greater inhibition, which persisted for at least 48 hr after partial hepatectomy. Rats chronically fed ethanol for 30 days also failed to achieve a hepatic proliferative response to either partial hepatectomy or D-galactosamine induced hepatitis comparable to isocaloric pair-fed controls. These investigations suggest that there may be a certain metabolic state in the hepatocyte cell cycle which is most susceptible to the action(s) of ethanol; inhibition of liver regeneration by acute or chronic ethanol consumption may result in delayed recovery from prior or coincident liver injury.
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PMID:Effect of acute and chronic ethanol intoxication on hepatic regeneration. 719 26

The effect of Silymarin (Legalon) upon liver lesions was investigated using four experimental models: In acute galactosamine-hepatitis, Silymarin administration achieved protection of the liver structure (electron-microscopy included), liver cell glycogen, RNA and enzymatic activity, Galactosamine-depressed gluconeogenesis in the isolated perfused rat liver was significantly preserved by Silymarin treatment. In lead and cadmium poisoning the structural damage and histochemical and histoenzymatic changes were partly but significantly prevented. The complex noxious effects of Imuran overdoses were favourably influenced by Silymarin, without diminishing the cytostatic-immunosuppressive action of Imuran.
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PMID:Effect of silymarin on experimental liver lesions. 733 95


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