Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The acute effects of the PCB (polychlorinated biphenyls) mixture (Aroclor 1254) on microsomal enzymes and on synthesis and turnover of microsomal and cytoplasmic lipids of rat liver were investigated. Six daily i.p. injections of 25 and 50 mg PCB/kg body weight resulted in increased liver weight and liver to body weight ratios. When compared to controls PCB treatment resulted in a six-fold increase in amount of cytochrome P-450. Activities of NADPH-cytochrome c reductase, ethylmorphine demethylase and inosine diphosphatase were increased whereas glucose-6-phosphatase values were decreased by PCB exposure. Analysis of liver homogenate and microsomal fraction revealed an increase in lipid in PCB-exposed animals. Phospholipids, cholesterol and triglyceride were significantly increased after PCB exposure; however, the greatest percentage increase was seen in the triglyceride pool. The finding of an increase in microsomal triglyceride to phospholipid ratios with exposure to PCB is suggestive of an increase in membrane-enclosed lipid (liposomes). Studies with labelled glycerol indicated that the PCB-induced fatty liver resulted from increased half life but not increased synthesis of liver lipid moieties. The rate of incorporation of leucine into microsomal membrane and albumin was somewhat enhanced in rats exposed to PCB indicative of increased protein synthesis. Morphological studies showed increased occurrence of lipid material, both in cytoplasmic droplets and within rough and smooth-surfaced endoplasmic reticulum. Proliferation of smooth endoplasmic reticulum and flattened Golgi cisternae with no secretion granules containing lipoprotein particles characterized the liver from animals exposed for 6 days. The increase in lipid within membranes of the endoplasmic reticulum together with the flattened Golgi lacking typical secretory vesicles indicates a defect in transport of lipoproteins from the endoplasmic reticulum to the Golgi apparatus and may be the cause of the PCB-induced fatty liver.
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PMID:Studies on the cellular toxicity of polychlorinated biphenyls (PCBs). I. Effect of PCBs on microsomal enzymes and on synthesis and turnover of microsomal and cytoplasmic lipids of rat liver- a morphological and biochemical study. 9 1

The mechanism of liver enlargement and anti-fatty liver effect of NKK-105 in the rat were investigated by the mesurement of drug-metabolizing enzyme activities and morphological changes in liver tissue detected using electron microscopy. A single administration of NKK-105(250, 500, 1000 mg/kg, p.o.) induced an apparent increase in liver weight. The elevation of aminopyrine demethylase activity and slight increase in microsomal cytochrome b5 and cytochrome P-450 content were seen with the administration of NKK-105. NKK-105 inhibited lipid peroxide formation in mitochondrial and microsomal fractions. Total lipid content of liver decreased at 12 hr after the administration of NKK-105. Lipid peroxide formation in mitochondrial and microsomal fractions was markedly inhibited by the addition of NKK-105 (1 X 10(-3)M), in vitro. Disarrangement of rough endoplasmic reticulum and increase in smooth endoplasmic reticulum were observed by the administration of NKK-105. The decrease in drug-metabolizing enzymes caused by CCl4 or ethionine was protected in the combination with NKK-105. NKK-105 markedly inhibited the elevation of lipid peroxide formation caused by CCl4 or ethionine. Similar effects on lipid peroxide formation were also obtained in vitro. These results suggest that the enlargement induced by NKK-105 indicates a functional not a toxic response. The inhibition of lipid peroxide formation in mitochondrial and microsomal fractions may thus play an important role in the mechanism of anti-fatty liver effect of NKK-105 on the CCl4 or ethionine-induced fatty liver.
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PMID:[Effects of diispropyl 1, 3-dithiol-2-ylidene malonate (NKK-105) on the drug-metabolizing enzymes and fine structure of rat liver (author's transl)]. 12 Feb 99

The role of liver size in drug metabolism was investigated in 34 chronic alcoholics and 28 controls by comparing antipyrine half-life with biopsy content and total amount of hepatic cytochrome P-450 (P-450) and liver weight. Liver size was significantly greater in alcoholics than in controls. Total P-450 was increased and antipyrine metabolism was enhanced in alcoholics with normal histology of the liver. In subjects with alcoholic hepatitis or cirrhosis, the antipyrine half-life was prolonged and P-450 was decreased. Alcoholics with fatty liver had a reduced P-450 content, but the total amount of P-450 and the antipyrine half-life were normal. The results demonstrate in alcoholics that an enlarged liver of normal histological appearance is associated with enhanced drug metabolism. In subjects with fatty liver the drug metabolizing capacity per unit weight of liver is often impaired, but the increase in liver size leads to undisturbed total oxidizing capacity and normal in vivo metabolism. In alcoholic hepatitis drug metabolism is impaired in spite of hepatomegaly. In cirrhosis the enlargement of the liver appears to compensate for the decreased P-450 content resulting in only slightly decreased total P-450, and the severly impaired in vivo drug metabolism may be due to derangement of blood flow.
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PMID:Liver size and indices of drug metabolism in alcoholics. 63 35

Serum zinc and copper levels were studied in relation to in vitro and in vivo drug metabolism in 25 alcoholics, in whom various diseases of the liver had been diagnosed by histology. Serum zinc was elevated in alcoholics with normal or fatty liver and was low in those with alcoholic hepatitis or cirrhosis. There was a significant positive correlation between serum zinc and cytochrome P-450 content of liver biopsies. The relationship between zinc and antipyrine half-life was significant and non-linear. Serum copper level was elevated in all the alcoholics and no significant relationship could be found between copper and drug metabolism in alcoholics. The findings suggest parallelism between changes in serum zinc and indices of drug metabolism in alcoholics.
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PMID:Serum zinc and serum copper and indices of drug metabolism in alcoholics. 92 28

Cytochrome P-450 dependent monooxygenases play a dual role for xenobiotic metabolism. On one hand they initiate the primary rate limiting step for the elimination of a bulk of drugs and organic chemicals. On the other hand they catalyze the formation of toxic metabolites from chemical carcinogens and many other toxic chemicals. Numerous studies have shown that their activity in animals is subject to the influence of various modifying factors, such as strain, species, sex, age, diurnal rhythm and the effect of enzyme inducers. Less is known about the influence of these factors on human cytochrome P-450 enzymes. Here we report the results of an extended study on human liver cytochrome P-450 performed with liver biopsies of 178 individuals taken for diagnostic purposes. The enzymatic activity was determined by the aldrin epoxidase assay indicating a variety of enzymes inducible by phenobarbital and by glucocorticoid and androgenic hormones. The frequency histogram of individual aldrin epoxidase activities showed a unimodal distribution and a variation factor of 100 between maximal and minimal activity. Individuals with severe liver diseases, such as cirrhosis and fatty liver, exhibited a 50% loss of enzyme activity. Age and sex did not significantly influence the enzyme activity. No significant correlation was observable between the rate of aldrin epoxidation and debrisoquine 4-hydroxylation, a prototype of a genetically controlled cytochrome P-450 reaction. We assume that the broad interindividual variation of epoxidase activities is more likely due to the influence of exogenous and endogenous inducers rather than to a genetic polymorphism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endogenous and exogenous factors modifying the activity of human liver cytochrome P-450 enzymes. 144 64

The effect of chronic exposure to micromolar concentrations of Aroclor 1254 (Aro) on the hepatic lipid metabolism was studied in long-term cultures of adult rat hepatocytes. Hepatocytes were cocultivated with mitomycin C-treated 3T3 cells and exposed for 2 wk to Aroclor 1254 concentrations ranging from 0.01 to 20 micrograms/ml. The Aro-exposed cultures showed intracytoplasmic lipid droplets and a maximum increase of 55% in the triglyceride (TG) content and of 4.4-fold in the cytochrome P-450 content. Labeling studies with [14C]acetic and [14C]oleic acid showed no changes in the uptake of fatty acid and TG precursors by the Aro-treated cultures; the synthesis of cellular lipids from [14C]acetic acid was slightly inhibited by Aroclor 1254, but that from [14C]oleic acid was increased, specially for TG (37%). The secretion of total lipids and TG was 2.1- and 2.7-fold lower, respectively, in the cultures treated with 20 micrograms/ml of Aroclor 1254, resulting in an increase of 1.9-fold in the intracellular content of TG. The synthesis of cellular proteins labeled with [3H]leucine was unchanged in the Aro-treated cultures, but the secretion of exportable proteins was 1.7-fold lower in the cultures treated with 20 micrograms/ml of Aroclor 1254. Our results showed that long-term exposure to in vivo relevant concentrations of Aroclor 1254 produced morphological and biochemical changes in cultured hepatocytes, like those described in vivo, and intracellular TG accumulation due mostly to impaired secretion of TG by the hepatocytes. Our results also suggest that this culture system could be useful for the screening of toxic agents producing fatty liver and the study of the involved mechanism(s).
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PMID:Triglyceride accumulation in long-term cultures of adult rat hepatocytes by chronic exposure to Aroclor 1254. 249 54

In liver biopsy material of eighty-nine patients with suspected liver disease the drug-metabolizing function was investigated. The capacity of the liver to oxidatively metabolize drugs was assessed by determination of cytochrome P-450 dependent monooxygenase activity in vitro. The biotransformational function of these microsomal enzymes was tested with compounds representing the activity of oxidative drug metabolism (7-ethoxycoumarin, p-nitroanisol and cytochrome c). From the eight-nine patients sixty-one had various liver diseases not related to ethanol and twenty-eight abused ethanol. When both groups were matched for age, sex, smoking, treatment with sedatives, drugs and degree of liver damage the alcoholic group had significantly higher activities of 7-ethoxycoumarin O-deethylase (EOD: 76.9 +/- 31.1 pmol min-1 mg-1 protein, mean +/- SD) than the non-alcoholic liver disease group (42.7 +/- 14.1). The inducing effect of ethanol was most striking on the EOD activity, less for the O-demethylation of p-nitroanisol (PNA) and not present for the NADPH-cytochrome c reductase. The induced patients were analysed in detail to find out which factors were responsible for the observed scatter of enzyme activities within the alcoholic group. Alcoholics with fatty liver (n = 7) had the highest EOD activities (108.9 +/- 25.0), patients with alcoholic hepatitis (n = 10) had significantly less activity (66.0 +/- 1.9) than the former group. However, alcoholics without liver damage (n = 6) had activities not significantly different (46.0 +/- 15.8) from controls (39.4 +/- 9.1). These subgroups among the alcoholics were comparable in terms of sex, age, smoking and drinking habits.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inducing efficacy of ethanol on hepatic drug metabolizing enzymes in patients. 309 41

The sulphur-containing drug, di-isopropyl-1,3-dithiol-2-ylidenemalonate (Malotilate) protects against the increase in hepatic triglyceride concentration after acute ethanol administration (either 6 g/kg p.o. or 2 g/kg i.p.) in rats. The compound had no influence on the increased hepatic NADH:NAD ratio (measured as the lactate:pyruvate and 3-hydroxybutyrate:acetoacetate ratios) after acute ethanol dosing (2 g/kg i.p.), but was found to lower hepatic acetaldehyde concentrations and prevent some of the disturbances in lipid metabolism observed in liver slices from ethanol-treated animals (e.g. decreased oxidation of [1-14C]palmitate to 14CO2) after this ethanol dose. The drug did not inhibit ethanol metabolism in this acute experiment. Administration of Malotilate to Wistar rats (100 mg/kg/day orally) during chronic feeding of ethanol as 36% of the total calorie intake in a liquid diet, resulted in a lower intake of the alcohol-containing diet by ethanol-fed animals and reduced body weight gain in rats which received the drug, without blood ethanol levels or the ethanol intake (expressed in g/kg body weight/day) being affected. In ethanol-fed animals, Malotilate prevented the production of fatty liver and the adaptive increase in the ethanol elimination rate (EER) normally seen in ethanol-fed animals, although the drug actually caused a slight increase in EER in glucose pair-fed controls. Malotilate did not significantly decrease the degree of induction of microsomal cytochrome P-450 by ethanol, but the increase in aniline hydroxylation was much less marked in animals receiving ethanol and Malotilate, suggesting that the activity of the inducible microsomal ethanol oxidising system (MEOS) may be reduced by the compound. Determination of hepatic acetaldehyde concentrations during ethanol feeding, and during an acute ethanol challenge test following long-term ethanol treatment showed that the compound significantly lowered the level of this ethanol metabolite in the liver under both circumstances. This reduction of hepatic acetaldehyde concentrations, probably resulting in part from the reduced EER as well as increased low-Km aldehyde dehydrogenase activities and glutathione contents seen in the livers of Malotilate-treated rats, are possible mechanisms by which the drug protects against triglyceride accumulation after ethanol administration.
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PMID:The effect of di-isopropyl 1,3 dithiol-2-ylidenemalonate (malotilate) on the hepatic changes induced by ethanol administration in the rat. 314 67

Chronic ethanol consumption results in the induction of a specific hepatic cytochrome P-450 (P450IIE1). However, since compounds other than ethanol (i.e., acetone) can also serve as P450IIE1 inducers, and since ethanol given with a normal fat-containing (35% of energy) diet is associated with acetonemia, hepatic steatosis and decreased body weight gain, the question has been raised whether induction is mediated specifically by ethanol or whether it might represent a nonspecific response to these other factors. This was investigated by varying both the mode of ethanol administration and the composition of the diet. By administering ethanol in the drinking water, or as part of a low-fat (5% of energy) liquid diet, a significant induction of P450IIE1 and of the activities of the microsomal ethanol oxidizing system and p-nitrophenol hydroxylase was demonstrated in the absence of any significant increase in blood acetone with minimal increase in liver total lipids. Induction of P450IIE1 was comparable with the low or normal fat-containing diets, but MEOS activity rose more with the latter, possibly reflecting a potentiating effect of dietary fat on ethanol oxidation by P-450 enzymes other than P450IIE1. When the lack of weight gain of the alcohol fed animals was mimicked in controls by decreasing the amount of diet ingested, no induction was observed. Varying the pattern of liquid diet feeding had no demonstrable differential effect. Thus, the induction of P450IIE1 after chronic ethanol consumption can be attributed to ethanol itself, but dietary fat can potentiate the induction of the microsomal ethanol oxidizing system and of p-nitrophenol hydroxylase.
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PMID:Role of acetone, dietary fat and total energy intake in induction of hepatic microsomal ethanol oxidizing system. 318 73

The effect of fibrosis on drug metabolism in alcoholic liver disease was evaluated in a comparison of the concentrations of serum aminoterminal propeptide of type III procollagen and basement membrane (BM; 7S domain of type IV collagen and laminin) antigens with in vitro (cytochrome P-450) and in vivo (antipyrine) drug metabolism in 67 alcoholics classified by liver histology. Alcoholics with intact or fatty liver had rapid or normal drug metabolism and normal collagen metabolism. Alcoholics with a fatty liver plus fibrosis or active cirrhosis had reduced drug metabolism and elevated levels of serum markers for collagen and BM metabolism. Alcoholics with inactive cirrhosis who had received therapy with enzyme inducers had a tendency toward normal drug and collagen metabolism parameters. Antipyrine metabolism, but not P-450 content, was related to the levels of serum type III collagen and BM markers. The fibrotic process, especially BM formation, creates a mechanical barrier that may prevent contact between blood and hepatocytes, thus delaying substrate availability.
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PMID:Fibrotic process and drug metabolism in alcoholic liver disease. 372 Jan 78


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