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Biomedical subjects

C S Lieber

Publications and source records attributed to C S Lieber.

At least 289 records · Page 16Linked to original sources
PubMed1985

New pathway for retinol metabolism in liver microsomes.

Rat liver microsomes were discovered to actively oxidize retinol to polar metabolites, including 4-hydroxyretinol, in a system requiring oxygen and NADPH. Involvement of cytochrome P-450 was indicated by CO and SKF-525A inhibition and reconstitution of this system with purified forms of cytochrome P-450 (b and f). Addition of excess unlabeled retinoic acid did not decrease the specific activity of the products formed from labeled retinol, suggesting that retinoic acid is not involved as an intermediate step. Microsomal inducers (such as phenobarbital) strikingly enhanced the activity of the system, resulting in 5-10-fold increased rates of retinol degradation. Furthermore, microsomal substrates (such as benzphetamine) inhibited microsomal retinol metabolism. This new pathway of retinol metabolism in liver microsomes may explain, at least in part, vitamin A-drug interactions, including drug-induced hepatic depletion of vitamin A.

Animals↗
PubMed1985

Association between amino acid alterations and hallucinations in alcoholic patients.

Because available evidence suggests that alterations in the serotonergic as well as dopaminergic tones underlie hallucinatory activity, we decided to investigate whether serotonin and dopamine pathways are modified in alcoholics with a history of hallucinosis. Brain serotonin has been shown to depend on the plasma ratio of its precursor tryptophan over other amino acids competing with it for brain entry. Similarly, brain dopamine depends on the plasma ratio of its precursors phenylalanine and dopamine over their competitors. Amino acid abnormalities are common in alcoholics. For this reason, we assessed whether alcoholics who had experienced hallucinations have alterations in amino acids believed to be associated with neurotransmitter modifications. Patients with a history of hallucinations were found to have a tryptophan ratio significantly lower than that of patients without such a history, and a tyrosine + phenylalanine ratio significantly higher. These data suggest that amino acid abnormalities believed to result in decreased brain serotonin and in increased brain dopamine render certain individuals more vulnerable to hallucinatory experiences.

Adult↗
PubMed1985

Chronic ethanol consumption alters rat liver plasma membranes and potentiates release of alkaline phosphatase.

The aim of this study was to investigate possible mechanisms involved in the elevation of serum alkaline phosphatase activity in alcoholics. Male Sprague-Dawley rats were pair-fed nutritionally adequate liquid diets containing ethanol as 36% of energy or an isocaloric amount of carbohydrate for 4-5 wk. Serum alkaline phosphatase activity was increased moderately but significantly. Hepatocytes isolated from ethanol-fed animals exhibited pronounced morphologic alterations of their plasma membranes by scanning electron microscopy and a reduced content of alkaline phosphatase despite an increase in total liver alkaline phosphatase content. Chronic ethanol feeding also potentiated the release of alkaline phosphatase from the cells during incubation with 50 mM ethanol. Furthermore, chronic ethanol feeding resulted in reduced recovery of alkaline phosphatase in hepatic plasma membranes isolated by sucrose gradient centrifugation but did not affect the recoveries of other plasma membrane markers (5'-nucleotidase and Na+,K+-adenosine triphosphatase) nor the subcellular distribution of alkaline phosphatase in the nuclear, mitochondrial, microsomal, and cytosolic fractions. These findings suggest that the increased serum alkaline phosphatase levels observed in response to chronic ethanol feeding may be due, at least in part, to increased lability of this plasma membrane enzyme.

Alkaline Phosphatase↗
PubMed1985

Increased type I procollagen mRNA levels and in vitro protein synthesis in the baboon model of chronic alcoholic liver disease.

We have investigated the molecular mechanisms responsible for the histologic changes induced by ethanol in the baboon model of alcoholic liver disease. Eleven ethanol-fed baboons and their pair-fed controls had histology evaluated and RNA extracted from percutaneous liver biopsy specimens. In 6 of the ethanol-fed animals, fatty liver developed, but no significant differences were found when the RNA from the control and ethanol-fed livers was translated in the reticulocyte lysate system or analyzed with specific cDNA probes. Five of the baboons given ethanol, however, developed significant fibrosis. Molecular evaluation revealed that the RNA from these livers was more active in in vitro protein synthesis, and the type I procollagen mRNA content was significantly higher per microgram of liver RNA as determined by hybridization analysis (183% +/- 23% SEM of control, p less than 0.02). In addition, there were higher levels of albumin mRNA content in the livers of ethanol-fed baboons that developed fibrosis (180% +/- 21% SEM of control, p less than 0.05). There was no change, however, in the levels of beta-actin mRNA, a representative constitutive protein. These findings in the baboon model of alcoholic fibrosis show that ethanol consumption increases type I procollagen mRNA, which may foster fibrogenesis; increases albumin mRNA content without causing an increase in serum albumin; and induces no change in levels of beta-actin mRNA. These studies also show that percutaneous needle biopsy can supply sufficient tissue to evaluate molecular changes in human liver disease.

Actins↗
PubMed1985

Pathogenesis of precirrhotic portal hypertension in alcohol-fed baboons.

To study mechanisms and anatomic correlates of precirrhotic portal hypertension, we measured portal pressure either at laparotomy (in the portal vein) or by hepatic vein catheterization (wedge pressure) in 24 pairs of baboons fed 50% of energy either as ethanol or isocaloric carbohydrate (controls) for 4 mo-9 yr. On liver biopsy 7 had simple fatty liver; none had portal pressure exceeding the control range (2.7-13.0 cmH2O). The remaining 17 alcohol-fed baboons had fibrous tissue deposition around the terminal hepatic venules and adjacent sinusoids. The mean portal pressure was significantly increased (15.0 +/- 1.4 cmH2O) compared with the value in baboons with fatty liver (9.6 +/- 0.9 cmH2O) and in controls (8.0 +/- 0.6 cmH2O), with 8 animals exceeding the control range. Estimated hepatic blood flow was unchanged. Alcohol feeding resulted in increased hepatocyte size in both the fatty liver and fatty liver with fibrosis group; however, portal pressure did not correlate with alterations of cell size, liver volume, hepatic triacylglycerol, and protein contents. By contrast, for veins of comparable size, there was a significant correlation (r = 0.6666, p less than 0.01) between the thickness of the perivenular fibrous rim and portal pressure. Perivenular fibrosis was commonly associated with adjacent perisinusoidal fibrosis and this lesion also correlated with portal pressure. Furthermore, if one postulates that increased cell size causes enhanced pressure with secondary fibrosis, the latter should have first occurred "upstream," in the mid and portal zones. Sequential biopsy specimens, however, showed that fibrosis first appeared in the perivenular areas, suggesting that, in most instances, increased pressure is in fact secondary to the perivenular fibrosis.

Animals↗
PubMed1985

The effects of ethanol and diet on hepatic and serum gamma-glutamyltranspeptidase activities in rats.

Rats fed pelleted nonpurified diets had significantly higher hepatic gamma-glutamyltranspeptidase (GGTP) activities than those fed liquid diets, with no difference in serum GGTP activities. However, levels of both hepatic and serum GGTP activity were higher in rats fed ethanol than in those fed liquid diets without ethanol. In addition, hepatic GGTP levels varied inversely with dietary carbohydrate content. These findings suggest that factors other than a mere increase of liver GGTP may be responsible for the elevated serum levels of this enzyme seen after chronic ethanol consumption and that dietary carbohydrate levels influence hepatic GGTP levels.

Alcohol Drinking↗
PubMed1985

Effects of chronic ethanol intake on mobilization and excretion of cholesterol in baboons.

To investigate the effects of chronic ethanol administration on the mobilization and excretion of cholesterol, turnover and balance studies were carried out in baboons pair-fed cholesterol-free diets containing 50% of energy either as ethanol or as additional carbohydrate for several years. Ethanol feeding increased free cholesterol in all plasma lipoprotein fractions, and esterified cholesterol in very low density lipoprotein, intermediate density lipoprotein, and high density lipoprotein (HDL). The major increase occurred in HDL, mainly as esterified cholesterol. The latter was associated with decreased transfer of esterified cholesterol from HDL to low density lipoprotein. By contrast, the smaller increase in HDL-free cholesterol was associated with increased turnover in the plasma, increased splanchnic uptake, and increased fecal excretion of plasma cholesterol, mainly as neutral steroids. Cholesterol extraction predominated over release in the splanchnic vascular bed, suggesting that the excess of cholesterol excreted in the feces originated in extrasplanchnic tissues. Thus, these findings indicate that alcohol consumption favors mobilization of tissue free cholesterol for hepatic removal and excretion. By contrast the increase in HDL-cholesterol (mainly esterified) appears to be a poor indicator of cholesterol mobilization.

Administration, Oral↗
PubMed1985

Isolation and culture of myofibroblasts from rat liver.

Successful isolation and culture of myofibroblasts from rat liver is described for the first time. After collagenase digestion of livers, obtained from rats fed regular laboratory chow diet as well as control and vitamin A-supplemented liquid diets, cells were separated on a Percoll density gradient. Cells characterized as myofibroblasts by electron microscopy were cultured in a Dulbecco's modified Eagle's medium. Characteristic features of myofibroblasts (abundant myofibrils) with dense bodies, indented nucleus, basal lamina-like structure, capacity to synthesize types I, III, and IV collagens and laminin were demonstrated in both primary and secondary cultures.

Actin Cytoskeleton↗
PubMed1984

Interaction of ethanol with acetaminophen metabolism in the baboon.

To evaluate the effects of ethanol on acetaminophen metabolism and toxicity, twelve female baboons were studied using three experimental designs. In the first one, animals fed ethanol chronically and their pair-fed controls received acetaminophen intravenously (40 mg/kg), and drug metabolism was studied for 6 hr in blood and urine. Elimination of acetaminophen from plasma was accelerated significantly in baboons fed alcohol chronically, and urinary excretion of mercapturic acid conjugate was increased. In the second, the experiments were repeated with the addition of ethanol infusion (120-160 mg/kg/hr). During ethanol infusion, elimination of acetaminophen from plasma was still accelerated significantly in baboons fed alcohol chronically. In the third experimental design, four pairs of baboons fed an alcohol or an isocaloric control liquid diet received, in addition, acetaminophen (85 mg/kg/day) in their respective liquid diets for 2 weeks. Liver histology was studied before and after acetaminophen feeding; SGPT, SGOT, SGDH, acetaminophen blood levels and acetaminophen urinary metabolites were also assessed. No morphological or functional liver alterations were found after chronic acetaminophen treatment, and urinary excretion of mercapturic acid conjugate was not increased in baboons fed alcohol chronically. Thus, our results in primates confirm that chronic ethanol consumption increases, whereas acute ethanol administration decreases, the excretion of mercapturic acid conjugate. When acute and chronic ethanol administration were combined, the effects tended to cancel each other out. A dose of acetaminophen which maintained blood levels similar to those recommended for humans did not produce deleterious effects in baboons drinking alcohol.

Acetaminophen↗
PubMed1984

The isolation and properties of mitochondria from rat pancreas.

A technique for the isolation of functional rat pancreatic mitochondria is described. The resultant mitochondrial preparations contained oligomycin-insensitive Mg2+-ATPase activity and coupled respiration could only be demonstrated in the absence of Mg2+ and in the presence of EDTA.

Adenosine Triphosphatases↗
PubMed1984

Depression of biliary glutathione excretion by chronic ethanol feeding in the rat.

The effects of chronic alcohol feeding on biliary glutathione excretion were studied in rats pair fed diets containing either ethanol (36% of total energy) or isocaloric carbohydrate for 4-6 weeks. An exteriorized biliary-duodenal fistula was established and total glutathione (GSH) and oxidized glutathione (GSSG) were measured. A significant decrease was observed in rats fed alcohol chronically compared to their pair fed controls in the biliary excretion of GSH (55.7 +/- 37.0 vs 243.1 +/- 29.0 micrograms/ml bile, p less than 0.025) as well as biliary GSSG (12.5 +/- 5.0 vs 49.9 +/- 8.0 micrograms/ml bile, p less than 0.05) and in bile flow (23.1 +/- 1.6 vs 29.2 +/- 1.3 micrograms/min, p less than 0.05). An acute dose of ethanol tended to exaggerate the decrease on biliary GSH and GSSG in the two groups of animals. The depression in biliary GSH could not be attributed to decreased GSH synthesis since S35-L-methionine incorporation into hepatic and biliary GSH was unchanged or even increased after chronic ethanol feeding.

Animals↗
PubMed1984

Ethanol metabolism in vivo by the microsomal ethanol-oxidizing system in deermice lacking alcohol dehydrogenase (ADH).

To assess the importance of non-ADH ethanol metabolism, ADH-negative and ADH-positive deermice were fed liquid diets containing ethanol or isocaloric carbohydrate for 2-4 weeks. Blood ethanol disappearance rate increased significantly after chronic ethanol feeding in both strains. Although at low ethanol concentrations (between 5 and 10 mM) there was no significant difference between ethanol-fed and pair-fed control animals, at high ethanol concentrations (between 40 and 70 mM) blood ethanol elimination rates were increased significantly after chronic ethanol feeding in both ADH-positive and ADH-negative animals. There was no significant effect of the catalase inhibitor 3-amino-1,2,4-triazole on the ethanol elimination/rates in both strains. Whereas catalase and ADH activities were not altered after chronic ethanol treatment, the activity of the microsomal ethanol-oxidizing system (MEOS) was enhanced three to four times in both strains, and microsomal cytochrome P-450 content was also increased significantly. When MEOS activity was expressed per cytochrome P-450 content, it was higher in ADH-negative than in ADH-positive animals, and it increased after ethanol administration. When microsomal proteins were separated by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis, ethanol-fed animals had a distinct band which reflected the increase in microsomal cytochrome P-450 content and seemed to reflect a unique form of cytochrome P-450 induced by ethanol. Thus, despite the absence of the ADH pathway, a large amount of ethanol was metabolized by MEOS in ADH-negative deermice; this was associated with increased blood ethanol elimination rates, enhanced MEOS activity, and quantitative and qualitative changes of cytochrome P-450.

Alcohol Dehydrogenase↗