Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many compounds, including established drugs, cause liver damage through biotransformation to reactive cytotoxic metabolites which bind covalently to hepatic macromolecules. The forms of expression of such injury include acute necrosis, chronic hepatitis, cirrhosis and neoplasia. Hepatotoxicity depends on the balance between metabolic activation and inactivation and reduced glutathione protects against the toxicity of some agents by trapping their reactive electrophilic metabolites. Toxicity is usually increased by induction and decreased by inhibition of hepatic microsomal enzymes.
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PMID:Reactive metabolites as a cause of hepatotoxicity. 638 40

In western industrialized countries ethanol is an important etiologic factor in the development of cirrhosis of the liver. Metabolic, immunologic and physico-chemical alterations of the hepatocyte due to ethanol are involved in the pathogenesis of alcoholic liver disease. However, the mechanisms by which ethanol damages the liver are far from clear. During the last two decades, the effect of ethanol on multiple biochemical pathways of the hepatocyte has been investigated intensively. The present paper is focusing on the metabolic aspects of alcoholic liver disease. In the first part of the review, special emphasis has been led on the metabolites of ethanol oxidation, while in the second part microsomal enzyme induction due to alcohol has been discussed. More than 90% of ethanol metabolism takes place in the liver via cytoplasmic alcoholdehydrogenase (ADH) and via a microsomal ethanol oxidizing system (MEOS). The products of these reactions are reduced nicotinadenine dinucleotide phosphate (NADH), acetaldehyde and acetate. NADH alters the redox state of the liver cell favouring all reductive processes. This shift in metabolic pathways results in hyperlactacidaemia, lactacidosis, ketosis and hyperuricaemia. Disturbances of the carbohydrate metabolism may lead either to hypo- or hyperglycaemia. The altered redox state also influences the metabolic pathways of lipid metabolism leading to lipid accumulation within the hepatocyte which can be morphologically observed as alcoholic fatty liver. In addition, porphyrin and collagen metabolism is also affected by the increased NADH/NAD+ ratio. On the other hand, acetaldehyde damages the microtubular system and the mitochondria. Acetaldehyde may also be responsible for the increased lipidperoxidation after chronic ethanol ingestion.
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PMID:[Metabolic aspects of alcoholic liver damage: 1984/5 update. 1. Epidemiology and alcohol metabolism]. 639 85

The effects of liver disease on caffeine plasma clearance (Cl) and on exhalation of 14CO2 following i.v. injection of 2 mu Ci of [3-methyl-14C]caffeine together with 125 mg of the unlabeled compound were measured in 15 patients with cirrhosis, 11 subjects with miscellaneous liver disease, and 10 normal volunteers. Compared to mean values for Cl (2.02 +/- S.D. 0.68 ml per min per kg) and t1/2 (3.8 +/- 0.9 hr) in normal volunteers, cirrhotics were characterized by highly significant reductions in Cl (to 0.76 +/- 0.40) and prolongation in t1/2 (to 13.7 +/- 13.0), whereas the volume of distribution (VD) remained relatively unchanged (0.57 +/- 0.16 vs. 0.64 +/- 0.13 liter per kg in normals). Cumulative 14CO2 production and specific activity of 14CO2 in breath decreased in parallel (r = 0.83) with Cl. Patients with miscellaneous liver disease exhibited only small changes in Cl and t1/2; however, 14CO2 parameters in breath appeared more sensitive in indicating the slight functional derangement. In view of the correlation (Rs = 0.83) of cumulative 14CO2 excretion with the initial disappearance constant for bromosulfophthalein, the caffeine breath test may be considered as a quantitative measure of hepatic microsomal activity; based on a surprisingly close, hyperbolic relationship between Cl and fasting caffeine plasma concentrations, the latter might serve as a simple guide to severity of liver disease.
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PMID:Caffeine: a model compound for measuring liver function. 642 Mar 3

To study the effects of alcoholic liver injury on the ability of ethanol to promote hepatic fat accumulation and hyperlipemia, baboons were pair-fed liquid diets containing 50% of energy either as ethanol or as additional carbohydrate (controls) for 1 to 7 years. Alcohol consumption produced triacylglycerol accumulation in the liver, hypertriacylglyceridemia, and various degrees of liver injury, including cirrhosis. At the early stages of fatty liver (with or without perivenular fibrosis), there was increased activity of microsomal diacylglycerol acyltransferase and of both microsomal and cytosolic phosphatidate phosphohydrolase, with no changes in glycerol-3-phosphate acyltransferase. With progression of the liver injury and development of septal fibrosis and/or cirrhosis, the rate of hepatic triacylglycerol accumulation and the magnitude of the hyperlipemia decreased, despite continuous ethanol intake. These changes were associated with disappearance of the increases in microsomal diacylglycerol acyltransferase and cytosolic phosphatidate phosphohydrolase activities, whereas those of microsomal phosphatidate phosphohydrolase remained elevated and glycerol-3-phosphate acyltransferase was unaffected. Thus, changes in the activity of two enzymes of the triacylglycerol-synthesizing pathway, namely the microsomal diacylglycerol acyltransferase and the cytosolic phosphatidate phosphohydrolase, may contribute to the differences in the rate of hepatic triacylglycerol accumulation and the degree of hyperlipemia during progression of the alcoholic liver damage.
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PMID:Hepatic triacylglycerol synthesizing activity during progression of alcoholic liver injury in the baboon. 649 27

In order to determine whether non-specific defects of protein synthesis account for reduced levels of cytochrome P-450 in cirrhotic liver, total microsomal protein synthesis and response to microsomal enzyme-inducing agents have been examined in rats. Cirrhosis was produced by administration of carbon tetrachloride (CCl4) and phenobarbitone for 10 weeks. Ten days after stopping these agents, cytochrome P-450 levels were 30% lower in cirrhotic liver than in controls (p less than 0.0001). However, total microsomal protein synthesis, determined in vivo by administration of [3H]-leucine, was similar in cirrhotic (1347 +/- 420 dpm/mg protein) and control (1317 +/- 303 dpm/mg protein) liver. Three separate types of microsomal enzyme-inducing agents, phenobarbitone, beta-naphthoflavone, and pregnenolone 16 alpha-carbonitrile, were administered to cirrhotic and normal rats. In both groups of animals increases of total cytochrome P-450 and selective changes of cytochrome P-450 isoenzymes (assessed by mixed function oxidase activity towards four substrates) were qualitatively and quantitatively similar. It is concluded that hepatocytes of cirrhotic rat liver synthesize microsomal protein at a normal rate but less of it is cytochrome P-450, and the entire process of enzyme induction is intact. Thus, it appears likely that altered regulation of basal levels of cytochrome P-450 rather than an altered response of the liver is responsible for the lowered cytochrome P-450 content of cirrhotic rat liver.
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PMID:Microsomal protein synthesis and induction of cytochrome P-450 in cirrhotic rat liver. 649 79

The 14C-aminopyrine breath test is a simple procedure for the non-invasive determination of the microsomal function of the liver. After the oral administration of a tracer dose of 2 microCi (74 kBq) of 14C-aminopyrine the 14CO2 activity of the expired breath air is determined in hourly intervals. There is a close correlation between its decrease and the elimination of aminopyrine from the plasma. Both the elimination constant of 14CO2 (Kbreath) and the maximal specific 14CO2 activity are useful quantitative parameters of the test. They allow conclusions as to the hepatic demethylation capacity. Both parameters were significantly lower in 15 patients with liver cirrhosis than in 12 control patients. The non-steroidal anti-inflammatory drug diclofenacsodium (Voltaren) did not significantly influence the demethylation of 14C-aminopyrine in 5 patients with rheumatic diseases and in 2 healthy probands. Further experiences with the breath test are necessary, especially with respect to its suitability for prospective investigations.
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PMID:[Experiences with the 14C-aminopyrine breath test in liver cirrhosis and under the effect of sodium diclofenac (Voltaren)]. 660 64

The function of microsomal destructing medicaments enzyme systems of the liver cell under hormonal contraception was objectified with the help of the aminopyrine test. After the oral administration of 9 mg dimethylaminoantipyrine (DMAAP) per kg body-weight together with 111 kBq 14C-DMAAP the elimination of 14CO2 was measured on the basis of the decrease of the radioactivity in the expiration air (respiration test). The plasma levels of DMAAP and its metabolites were measured, too. The two measurements lasted 5 hours. In contrast to a control group consisting of 8 women with healthy liver who were not ovulostatically treated (half-value time 14CO2-DMAAP 2.9 +/- 0.8 h, plasma 2.2 +/- 0.5 h) in 20 test women with healthy liver under ovulation inhibitors the elimination of 14CO2-DMAAP with 4.7 +/- 1.6 was clearly (alpha less than 0.01), the plasma elimination with 3.0 +/- 0.8 h was slightly retarded (alpha less than 0.05). In 19 patients with histologically ascertained chronic hepatopathies of above all insignificant degree of severity (13 degenerative lesions of liver parenchyma, 3 fatty livers stage I or II, 1 chronic active hepatitis each, chronic persisting hepatitis and cirrhosis) under hormonal contraception a half-value time of the 14CO2 elimination (alpha less than 0.001) prolonged to 5.0 +/- 1.5 h and a prolongation of the plasma elimination to 3.8 +/- (alpha less than 0.05). In 9 women in double examinations the 14CO2 elimination of the DMAAP after discontinuation of the application of ovulation inhibitors was compared with the values obtained under hormonal contraception and a regression of the retarded excretion in the expiration air (4.2 +/- 2.3 less than 5.1 +/- 1.2 h) and plasma (2.6 +/- 0.7 less than 3.4 +/- 1.7) was proved.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Hepatic clearance of aminopyrine in the evaluation of liver function in hormonal contraception]. 667 Mar 37

The authors have studied the action of fluorine, administered by inhalation, on the liver metabolism of a chemical carcinogen: dimethylnitrosamine (DMN). The results demonstrate a decrease in the level of cytochrome P450 and in the activity of benzo(a)pyrene hydroxylase in animals treated with DMN or DMN + HF. The greater inhibition in the presence of HF is paralleled by a decrease in the weight of the liver and in the synthesis of liver microsomal proteins. This reduction of activity (with the exception of dimethylnitrosamine demethylase which is unaffected) is supported by the result of the histological examinations showing two different types of lesion-necrotic toxic hepatitis and post-hepatitic cirrhosis - the frequency of which is much higher in the presence of fluorine.
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PMID:[Effect of HF on the hepatic metabolism of dimethylnitrosamine in the rat]. 667 13

Seventeen children with chronic active hepatitis and high serum titers of smooth-muscle or liver-kidney microsomal antibodies were given prednisone and azathioprine. Clinical and biochemical remission was obtained in all but two, who died of progressive liver failure. Evaluations in 14 children after a mean period of 22 months of treatment showed normal transaminase activity and gammaglobulin levels in 12, and serum autoantibody titers of less than 1: 100 in 10; liver histologic findings showed absence of inflammation in seven children, moderate portal or lobular inflammation in five, and minor features of aggressivity in two. Cessation of therapy was then attempted in nine children. Relapse occurred in all but one and could not be attributed to any previously recorded biologic or histologic feature. After follow-up of 18 months to 7 years, all but two patients are still receiving maintenance therapy with prednisone and azathioprine. Cirrhosis was present before treatment in 13 children and is now present in all but one. These results suggest that in most children with autoimmune chronic active hepatitis, immunosuppressive therapy can prevent further deterioration of liver function but must be pursued for several years before discontinuation is attempted.
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PMID:Treatment of autoimmune chronic active hepatitis in childhood. 672 13

Therapy with enzyme inducing drugs may improve the clinical state of alcoholics with liver cirrhosis. The histological changes associated with the therapy were investigated by comparing liver biopsies before and after phenobarbital and medroxyprogesterone acetate treatment, known inducers of hepatic microsomal enzyme system, in eight alcoholics with cirrhosis and two control groups, subjects with normal liver and endstage alcoholic cirrhosis. Pericellular collagen, determined morphometrically, reduced from a point value of 87.6 +/- 28.3 to 63.4 +/- 16.7 (p less than 0.01), while the fibrous septa as well as the non-fatty and fatty parenchyma did not alter significantly. Antipyrine metabolism, an index of hepatic cell function, improved from 17.4 +/- 6.4 to 45.6 +/- 22.2 ml/min (p less than 0.01). Although direct correlation between the decrease of pericellular collagen fibres and antipyrine metabolism was not significant (r = 0.410) the findings suggest that accumulation of pericellular collagen prevents mechanically and availability of the compound to the cell, thus delaying its metabolism.
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PMID:Pericellular collagen in alcoholics with liver cirrhosis. 705 84


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