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Biomedical subjects

C S Lieber

Publications and source records attributed to C S Lieber.

At least 343 records · Page 19Linked to original sources
PubMed1982

Hepatic aldehyde dehydrogenase activity in Peromyscus genetically deficient in alcohol dehydrogenase.

1. Hepatic aldehyde dehydrogenase (ALDH) activity was measured in two strains of deer-mouse, Peromyscus maniculatus. 2. There is no difference in the subcellular distribution of ALDH activity in the two strains. Animals of AdhN/AdhN genotype, lacking liver alcohol dehydrogenase (ADH), had 90% of total ALDH activity in the mitochondrial fraction compared to 94% for the AdhF/AdhF animals with normal ADH activity. Almost all of the remaining ALDH activity was in the hepatic cytosol with less than 1% in the microsomal fraction. 3. By contrast, in mice (Mus musculus) 43% of total hepatic ALDH activity was found in the cytosolic fraction and 55% in the mitochondrial. 4. It was concluded that the subcellular distribution of hepatic ALDH activity in Peromyscus does not vary with the presence or absence of ADH and that this ALDH distribution is not similar to that reported for other rodents.

Alcohol Dehydrogenase↗
PubMed1982

Changes in vitamin A status after acute ethanol administration in the rat.

To evaluate the effect of acute ethanol administration on vitamin A and retinol-binding protein (RBP) status, male Sprague-Dawley rats weighing 120-200 g were given an acute dose of ethanol (6 g/kg body weight, orally) or saline after a 15- to 18-hour fast. Hepatic vitamin A was decreased by 13% (P less than 0.025) 24 hours after ethanol administration. Serum vitamin A was increased 6 hours after the ethanol dose (P less than 0.005) with a 10-fold increase in retinyl ester concentration, whereas serum RBP was slightly decreased. Saline controls showed no changes. The increase in serum retinyl esters 6 hours after the ethanol dose was found in the lipoprotein fraction (density less than 1.21). When lipoprotein removal from plasma was blocked by Triton WR-1339 ethanol administration further enhanced serum retinyl ester concentration. In rats previously given [14C] retinol, hepatic 14C-labeled vitamin A was decreased, whereas in the kidney and adipose tissue it was increased 24 hours after ethanol administration. Thus, an acute dose of ethanol increases serum vitamin A and decreases hepatic vitamin A, most likely because of increased release from the liver or decreased uptake by the liver of retinyl esters as part of the lipoproteins.

Alcoholic Intoxication↗
PubMed1982

Mechanism for selective perivenular hepatotoxicity of ethanol.

Chronic alcohol administration to baboons results in perivenular lesions in the liver. To study possible mechanisms, the effect of ethanol on splanchnic oxygen consumption was measured. Acute ethanol administration increased splanchnic oxygen consumption in the control baboons, but the consequences of this effect on oxygenation of the perivenular zones were offset by a concomitant rise in blood flow, resulting in unchanged hepatic venous oxygen tensions. In alcohol-fed baboons, splanchnic oxygen consumption was not increased, either in the withdrawal state or after ethanol infusion. To study the magnitude of the shift in redox state induced by ethanol in the perivenular zones, we compared the effects of ethanol on the lactate/pyruvate ratio in hepatic venous blood (an approximation of that in perivenular hepatocytes) with the ratio in total liver. Prior to ethanol infusion, the lactate and pyruvate were the same in liver and in hepatic venous blood. By contrast, in all baboons, ethanol produced a much greater rise in the lactate/pyruvate ratio and decreased pyruvate more in hepatic venous blood than in total liver. Moreover, in isolated rat hepatocytes, the ethanol-induced redox shift was markedly exaggerated by oxygen tensions similar to those found in centrolobular zones. This suggests that the normally low oxygen tensions existing in perivenular zones exaggerate the ethanol-induced redox shift, a change which may contribute to the exacerbation of the damage in the perivenular area of the hepatic lobule.

Alcohol Drinking↗
PubMed1982

The feeding of alcohol in liquid diets: two decades of applications and 1982 update.

The technique of feeding ethanol as part of a totally liquid diet was invented two decades ago and its successful application for the intervening period is reviewed. This technique results in much higher ethanol intake than with conventional procedures. As a consequence, various complications observed in alcoholics were reproduced in animal models, including fatty liver, hyperlipemia, various metabolic and endocrine disorders, tolerance to ethanol and other drugs, physical dependence and withdrawal, the fetal alcohol syndrome and, in the baboon, liver fibrosis and cirrhosis. Variations of the liquid diet formulation are compared and three standardized basic formulas are being proposed for the rat: (1) a regular diet, comparable to the diet previously referred to as the "Lieber-DeCarli Formula" and suitable for most experimental applications, particularly those intended to mimic the clinical situation in which the various effects of alcohol occur in the setting of liver changes characterized by a fatty liver; (2) a low fat diet comparable in all respects to the preceding diet but with a lower fat content, intended to minimize the hepatic changes; and (3) a high protein formula particularly useful in those circumstances in which an oversupply of dietary protein might be recommended (i.e., pregnancy and lactation).

Alcoholism↗
PubMed1982

Effects of alcohol on hepatic transport of proteins.

Alcohol inhibits the secretion of protein from the liver. Chronic abuse results in intrahepatic accumulation of export-type proteins and decreased plasma levels. These effects appear to be mediated by acetaldehyde, an oxidation product of ethanol. Acetaldehyde is capable of interfering with the assembly of microtubules, a component of the cytoskeleton, the integrity of which is required for normal secretion. Protein retention and cytoskeletal alterations may contribute to manifestations of alcoholic liver disease, such as hepatomegaly, ballooning of the hepatocyte, portal hypertension, and development of Mallory bodies.

Acetaldehyde↗
PubMed1982

Hepatotoxicity of vitamin A and ethanol in the rat.

To study the possible hepatotoxicity of vitamin A supplementation and its potentiation by ethanol, rats were fed diets with either normal or fivefold increased vitamin A content, both with or without ethanol. Ethanol with a normal vitamin A diet produced the expected proliferation of the smooth endoplasmic reticulum and moderate mitochondrial lesions. Vitamin A supplementation by itself produced endoplasmic reticulum proliferation, slight enlargement of mitochondria, and moderate decrease in cytochrome oxidase activity and cytochrome aa3 content. The combination of high vitamin A and ethanol resulted in much more striking lesions, with giant mitochondria containing paracrystalline inclusions and depression of oxygen consumption in state-3 respiration with five different substrates, including palmitate and palmitoyl coA. The depression of fatty acid oxidation may have contributed to the lipid accumulation. The blood levels of vitamin A were unaffected whereas liver levels of vitamin A were increased by vitamin A supplementation and decreased by ethanol. As a net result the liver vitamin A content of the high-A-ethanol groups was not greater than that of the normal-A-control group, suggesting that a metabolite of vitamin A rather than vitamin A itself may have been responsible for the potentiation of vitamin A toxicity by ethanol. Mitochondrial toxicity reflected itself also in decreased content of various cytochromes and reduced activity of enzymes, including glutamate dehydrogenase. The activity of the latter was increased in the serum. Implications of these findings for the routine treatment of alcoholics with vitamin A and the monitoring for possible signs of toxicity are discussed.

Animals↗
PubMed1982

Activation of tryptophan pyrrolase after chronic alcohol administration.

We have recently found decreased plasma tryptophan levels in alcoholics as well as in baboons and rats fed alcohol chronically. In the present study we investigated changes in tryptophan pyrrolase which is considered to be rate limiting for tryptophan catabolism. Rats fed alcohol chronically showed an increased activity of the enzyme in the liver and an increased formation of kynurenine after administration of a tryptophan load. It is concluded that this enhanced enzymatic activity may be responsible, at least in part, for the depressed plasma tryptophan levels we observed.

Alcoholism↗
PubMed1982

Ultrastructure of initial stages of perivenular fibrosis in alcohol-fed baboons.

Perivenular fibrosis was studied in baboons pair-fed with alcohol containing or isocaloric control diets for up to 8.5 years, and biopsies were performed on the animals one to two times a year. The number and types of mesenchymal cells surrounding the terminal hepatic venules were examined at various stages of thickening of the rim of the terminal hepatic venules by light and electron microscopy. The number of mesenchymal cells increased with progression of fibrosis and showed good correlation with the thickness of the rim (r = 0.7435, P less than 0.001, n = 56). myofibroblasts were the most common mesenchymal cells. They were present around the terminal hepatic venules in the control animals and proliferated after alcohol. This was associated with increased deposition of collagen fibers around the terminal hepatic venules. This fibrotic process extended into the perisinusoidal space of the centrolobular areas, sometimes connecting with pericellular fibrosis and/or fat granuloma, which developed in the lobule. Thus, in baboons fed alcohol, perivenular fibrosis is associated with myofibroblast proliferation followed by collagen deposition. Myofibroblast proliferation appears to represent the earliest detectable precursor lesion leading to hepatic fibrosis in alcoholic liver injury.

Animals↗
PubMed1982

Perivenular fibrosis in alcoholic liver injury: ultrastructure and histologic progression.

Twenty alcoholic patients underwent sequential biopsy of the liver as part of their medical evaluation. Of the 10 patients with simple fatty liver, 9 showed no progression of the histologic lesion after 1-2 yr. By contrast, of 10 patients with perivenular fibrosis, of the 9 who continued to drink all showed progression. Laboratory parameters did not distinguish between these two groups at the time of initial biopsy. The ultrastructure of the perivenular lesion was evaluated in 11 patients. The thickness of the perivenular rim was variable, but there was a good correlation between the thickness of the perivenular rim and the number of mesenchymal cells surrounding the venules (correlation coefficient r = 0.7634, p less than 0.001). Myofibroblasts represented the most common cell type but there was also infiltration with other mononuclear cells. Collagen fibers surrounding myofibroblasts were observed in the perivenular fibrotic area. Thus, in the group of alcoholics who were investigated in this study, myofibroblast proliferation and collagen deposition around the terminal hepatic venule represent the first apparent lesions in the sequence of events leading to alcoholic cirrhosis.

Fatty Liver, Alcoholic↗
PubMed1982

Origin of breath acetaldehyde during ethanol oxidation. Effect of long-term cigarette smoking.

Oropharyngeal microflora and lung microsomes can produce acetaldehyde from ethanol. Therefore we evaluated the suitability of breath acetaldehyde analysis to estimate blood acetaldehyde. We found that in individuals who develop high acetaldehyde concentrations (over 50 micro M) after alcohol ingestion (such a s oriental "flushers"), the acetaldehyde concentration in end-expiratory air reflects the blood levels. However, in the majority of non-Oriental subjects who develop very small concentrations of acetaldehyde in the blood (less than 5 micro M), the production of acetaldehyde in the respiratory tract accounted for most of the acetaldehyde present in end-expiratory samples. Under the latter conditions, breath acetaldehyde did not correlate with blood levels. The production of acetaldehyde from ethanol in the respiratory tract was markedly exaggerated in long-term cigarette smokers. Rinsing the oropharyngeal cavity with pyrazole (an alcohol dehydrogenase inhibitor) prior to sampling reduced, but did not eliminate, the local contribution to breath acetaldehyde, especially in smokers. In baboons, blood acetaldehyde could be accurately estimated from breath analysis only when the upper respiratory tract was completely excluded by collecting the expired air through an endotracheal tube. Thus, to assess blood acetaldehyde, breath acetaldehyde measurements cannot be substituted for direct measurements, except for those few conditions known to be associated with very high blood levels.

Acetaldehyde↗
PubMed1982

Partial characterization of hepatic aldehyde dehydrogenase from the baboon.

The activities, isozymic forms, response to disulfiram and some physical and kinetic properties of hepatic aldehyde dehydrogenase (A1DH, [EC.1.2.1.3]) from baboons were investigated. A1DH specific activity was greater in mitochondria than in cytosol but cytosolic A1DH was more sensitive to disulfiram than mitochondrial A1DH. Gel isoelectric focusing revealed three major isozyme groups focusing between pH 4 and 7, two in mitochondria and one in cytosol. Isozyme profile differences between control and ethanol-fed baboons appeared chiefly in the cytosol. Cytosolic A1DH from a control baboon was purified 42 fold with a 21% yield by ammonium sulfate fractionation, ion exchange chromatography, and affinity chromatography. The enriched enzyme displayed non-linear kinetics with 10% of the total activity having a Km of 0.3 microM and 90% having a Km of 160 microM. pH for optimum activity was 9.0, molecular weight 290,000 and, between pH 6.8 and 8.0, Mg++ ions inhibited the A1DH activity in the cytosol.

Aldehyde Dehydrogenase↗