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)

Theophylline and its derivatives, such as aminophylline, have an established role as bronchodilators, although their mode of action in man is not clear. There is circumstantial evidence that therapeutic doses of theophylline may have a phosphodiesterase inhibiting effect, thus potentiating the effects of cyclic AMP. However, it remains to be established whether this is the primary mode of action of theophylline at the biochemical level. The pathways of theophylline metabolism have been clarified, although most of the enzymes involved have not been characterized. Hepatic microsomal enzyme induction by polycyclic hydrocarbons will increase the rate of theophylline elimination. There are a number of factors which influence theophylline clearance in adults, which is known to be highly variable. These factors include obesity, smoking habit, diet and the presence of such diseases as hepatic cirrhosis, acute pulmonary oedema, cor pulmonale and viral respiratory infection. There is a good correlation between plasma theophylline level and bronchodilator effect. This can be demonstrated at plasma levels as low as 5 microgram/ml, although optimal levels are usually greater than 10 microgram/ml. Unacceptable toxicity usually occurs in association with plasma levels greater than 20 microgram/ml. The maintenance of adequate plasma theophylline levels by the use of a sustained-release aminophylline tablet is discussed.
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PMID:Theophylline: biochemical pharmacology and pharmacokinetics. 22 Jan 19

Possible mechanisms whereby alcohol abuse and alcohol-related diseases may promote the development of cancer are analyzed. The mechanisms discussed include: (a) contact-related local effects on the upper gastrointestinal tract; (b) the presence of low levels of carcinogens in alcoholic beverages; (c) induction of microsomal enzymes involved in carcinogen metabolism; (d) various types of cellular injury produced by ethanol and its metabolites and their relationship to cancer, particularly in the liver; (e) the nutritional disturbances frequently associated with alcohol abuse. The relationship between alcohol-induced cirrhosis and hepatocellular carcinoma is also discussed, and case histories of patients seen at the Bronx Veterans Administration Medical Center with hepatocellular carcinoma in the absence of cirrhosis are reviewed. Data are presented demonstrating the induction, by chronic ethanol consumption, of microsomal enzymes which convert procarcinogens to carcinogens. These data were derived from experiments in which the ability of microsomes isolated from liver, intestine, and lung tissues of ethanol-fed and control rats to activate several test carcinogens was examined in the Ames Salmonella-mutagenicity test. The hypothesis is presented that ethanol-mediated induction of enzyme systems which activate procarcinogens to carcinogens in various tissues contributes to the enhanced incidence of cancer in the alcoholic.
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PMID:Alcohol-related diseases and carcinogenesis. 22 Nov 10

Hepatic metabolism of ethanol to acetaldehyde by the alcohol dehydrogenase pathway is associated with the generation of reducing equivalents as NADH. Conversely, reducing equivalents are consumed when ethanol oxidation is catalyzed by the NADPH dependent microsomal ethanol oxidizing system. Since the major fraction of ethanol metabolism proceeds via alcohol dehydrogenase and since the oxidation of acetaldehyde also generates NADH, an excess of reducing equivalents is produced. This explains a variety of effects following acute ethanol administration, including hyperlactacidemia, hyperuricemia, enhanced lipogenesis and depressed lipid oxidation. To the extent that ethanol is oxidized by the alternate microsomal ethanol oxidizing system pathway, it slows the metabolism of other microsomal substrates. Following chronic ethanol consumption, adaptive microsomal changes prevail, which include enhanced ethanol and drug metabolism, and increased lipoprotein production. Severe hepatic lesions (alcoholic hepatitis and cirrhosis) develop after prolonged ethanol consumption in baboons. These injurious alterations are not prevented by nutritionally adequate diets and can therefore be ascribed to ethanol rather than to dietary inadequacy.
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PMID:Differences in hepatic and metabolic changes after acute and chronic alcohol consumption. 24 Jul 42

The enzyme gamma-glutamyl transpeptidase is widely distributed throughout the body, notably kidney, seminal vesicles, pancreas, liver, spleen and brain. Being one of the enzymes of the gamma-glutamyl cycle, it is involved in aminoacid transport, catalysing a transpeptidation reaction between gamma-glutamyl peptides and most common amino acids. Methods of assay of the enzyme are based on its ability also to act on synthetic amides of glutamic acid; kinetic methods monitoring the release of p-nitroaniline from the substrate L-gamma-glutamyl p-nitroanilide are the most satisfactory. In diseases of the liver, the highest levels occur in association with cirrhosis, alcoholism, hepatic secondaries and cholestasis. As the enzyme is present in the endoplasmic reticulum of the hepatocyte, its activity is increased in situations leading to microsomal enzyme induction. Raised levels can also occur in pancreatitis, diabetes, myocardial infarction, congestive cardiac failure, chronic renal failure, cerebrovascular accidents, cerebral tumours and chronic obstructive pulmonary disease. Although the lack of specificity must be recognised, the estimation can be useful in the elucidation of some clearly defined problems arising during investigation of patients with suspected hepatic disease, especially where performed as part of a biochemical profile.
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PMID:Role of gamma-glutamyl transpeptidase activity in the diagnosis of hepatobiliary disease. 24 76

Chronic alcohol consumption results in early biochemical and ultrastructural alterations of the hepatocyte which in turn may lead to alcoholic fatty liver as well as alcoholic hepatitis and via the central hyaline sclerosis to fibrosis and cirrhosis of the liver. Already at the stage of the alcoholic fatty liver an isolated increase of serum gamma-glutamyltransferase activity can often be observed; it results from hepatic microsomal enzyme induction and may facilitate early recognition of alcoholic liver injury. To establish the diagnosis, however, a histological examination of the liver is necessary. The therapy of alcohol-induced liver injury is based upon an absolute alcohol abstinence since alcohol itself or one of its metabolites are hepatotoxic.
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PMID:[Clinical aspects of alcohol induced liver injury (author's transl)]. 35 67

The concentration of cytochrome P-450 and activities of the microsomal enzymes aryl hydrocarbon hydroxylase and ethylmorphine demethylase were measured in hepatic tissue obtained at biopsy from 69 patients. Antipyrine half-life (AP t1/2) was measured simultaneously as an in vivo marker of drug metabolism. Values for each index of the drug-metabolizing system varied greatly, but the mean values in groups of patients with mild hepatitis or inactive cirrhosis did not differ significantly from those of controls. Hepatic cytochrome P-450 content and aryl hydrocarbon hydroxylase activity were lower in patients with severe hepatitis or active cirrhosis than in controls, but ethylmorphine demethylase activity was unchanged in the patients. Drug ingestion was associated with enhancement of drug-metabolizing enzymes in all patients but those with severe liver disease; ethylmorphine demethylase activity was enhanced proportionately more than aryl hydrocarbon hydroxylase activity or cytochrome P-450 concentration. The observation that aryl hydrocarbon hydroxylase and ethylmorphine demethylase activities are influenced to a different extent by liver disease and also by drug ingestion indicates functional heterogeneity of the hepatic microsomal drug-metabolizing system in man. Correlations between t1/2 and hepatic drug oxidases were weak, even when allowance was made for variation in liver size. Thus, the rate of drug metabolism in vivo assessed by measuring AP t1/2 does not appear to be closely related to the activity of some hepatic drug-metabolizing enzymes.
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PMID:Drug metabolism in liver disease: activity of hepatic microsomal metabolizing enzymes. 48 96

A controlled study of the effects of glutethimide on antipyrine metabolism was performed to ascertain how patients with varying degrees of liver damage responded to microsomal enzyme inducing agents. The administration of 250mg glutethimide daily for one week resulted in significant enhancement of antipyrine metabolism in 4 patients with compensated cirrhosis and 5 patients with features of hepatic failure as well as 7 control subjects without liver disease. Even patients with very severe liver disease did undergo microsomal enzyme induction. Changes in antipyrine half-life after glutethimide were directly proportional to the original antipyrine half-life so that the greatest absolute alterations due to enzyme induction occurred in patients with the most severely impaired hepatic function. These results indicate that not only is antipyrine metabolism severely impaired in patients with liver failure, but elimination rates are markedly altered by enzyme inducing agents. Thus, although these results cannot be extrapolated to all inducers of hepatic microsomal enzymes nor to all drugs metabolized by microsomal oxidases, it is suggested that safe and effective management of drug therapy in these patients requires measurement of plasma levels.
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PMID:Enhancement of hepatic drug metabolism by glutethimide in patients with liver disease. 49 7

Different methods of performing the (14C) aminopyrine breath test have been assessed. A tracer dose of 2 muCi without a loading dose and with a single breath collection at two hours was the method selected, since it gave the best discrimination between patients with hepatocellular diseases and normal subjects (5.2 +/- 0.2%, mean +/- SEM). Reduced values occurred in patients with chronic active hepatitis (with and without cirrhosis) (1.5 +/- 0.2%), alcoholic cirrhosis (1.7 +/- 0.4%) and hepatitis (2.5 +/- 0.3%), and late primary biliary cirrhosis suggesting defective microsomal function with respect to demethylation. Normal results were common in early primary biliary cirrhosis. Two weeks of prednisolone therapy caused some improvement in the breath test in nine of 10 patients with chronic active hepatitis. It is concluded that the (14C) aminopyrine breath test is a simple test for detecting hepatocellular dysfunction, but has no obvious diagnostic advantage over the determination of serum aspartate transaminase and two hour post-prandial bile-acids.
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PMID:Assessment of the (14C) aminopyrine breath test in liver disease. 62 4

The urinary excretion of D-glucaric acid, a catabolite of glucuronic acid, is considered to be a reliable index of the state of hepatic microsomal enzyme activity. Because enzyme activity may be altered in liver disease, we examined the effect of liver disease on the excretion of this metabolite and its correlation with liver function tests. We studied 89 patients with nonhemolytic jaundice, 39 with viral hepatitis, 33 with obstructive jaundice, six with cirrhosis, and 11 patients with jaundice of mixed etiology. Glucaric acid excretion was significantly increased in all these patients as compared to controls, most pronounced in the obstructive jaundice group. No correlation was found between glucaric acid excretion and concentrations of bilirubin, albumin, globulin, aspartate aminotransferase, alkaline phosphatase, cholesterol, or gamma-glutamyltransferase in serum, even though the concentrations of these analytes did vary with the type of liver disease. We suggest that this increase in glucaric acid excretion is an indication of normal or even increased glucuronidation (UDP-glucuronosyltransferase activity), which occurs in liver disease.
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PMID:Increased D-glucaric acid excretion by jaundiced patients. 69 85

Using a micromethod, hepatic bilirubin UDP-glucuronyl transferase has been assayed in percutaneous needle biopsy samples obtained from patients with infectious hepatitis, postnecrotic cirrhosis, Gilbert's disease, noncirrhotic portal fibrosis (NCPF), granuloma of the liver, and extrahepatic portal vein obstruction. The results were compared with those obtained from 10 control subjects. Patients with cirrhosis and infectious hepatitis revealed normal bilirubin transferase levels, whereas those with Gilbert's disease showed significantly low enzyme levels. Many patients with NCPF, some with extrahepatic portal vein obstruction, and patients with granulomatous involvement of the liver demonstrated significantly low levels. This low hepatitic-enzyme activity was not associated with hyperbilirubinemia. The mechanism of such low values in NCPF and other disorders is not known. It is postulated that low heaptic-enzyme activity in noncirrhotic portal fibrosis is due to sparse smooth endoplasmic reticulum. This study also emphasizes that serum bilirubin may remain normal with very low hepatic-enzyme activity. Although induction of the microsomal enzyme bilirubin transferase was observed following phenobarbitone administration in noncirrhotic portal fibrosis, this was not apparent in patients with cirrhosis, possibly due to maximal enzyme induction having been achieved by endogenous substrate.
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PMID:Estimation of hepatic bilirubin UDP-glucuronyl transferase in patients with noncirrhotic portal fibrosis and liver disease: Significance and limitations. 81 Nov 12


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