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Biomedical subjects

C S Lieber

Publications and source records attributed to C S Lieber.

At least 217 records · Page 12Linked to original sources
PubMed1988

Chronic ethanol consumption inhibits repair of dimethylnitrosamine-induced DNA alkylation.

Chronic ethanol consumption causes a DNA repair deficiency. This was demonstrated in Sprague-Dawley rats injected with 14C-labeled dimethylnitrosamine after being pair-fed isocaloric, ethanol, or carbohydrate control diets for 4 weeks. Hepatic DNA was isolated from rats killed at intervals over a 36 hour period after administration of the nitrosamine and concentrations of alkylated guanine derivatives were measured. While N7-methylguanine was lost at equivalent rates from the DNA of both diet groups, 06methylguanine, a promutagenic lesion, persisted at higher levels for longer periods of time in the DNA from the alcohol-fed animals.

Alcoholism↗
PubMed1988

Molecular regulation of ethanol-inducible cytochrome P450-IIEI in hamsters.

Liver polysomal poly(A)+ RNA, isolated from hamsters treated with ethanol or pyrazole, was translated in vitro to determine the effect of these compounds on specific mRNA encoding P450-IIEI, an ethanol-inducible P450 isozyme. As assessed by immunoprecipitation of translation products, ethanol and pyrazole increased hepatic P450-IIEI mRNA levels by 160% and 45%, respectively, when compared to controls. In liver microsomes from the same animals, ethanol and pyrazole caused a two-fold increase in microsomal P450-IIEI protein and a two- to three-fold enhancement of microsomal ethanol oxidation and p-nitrophenol hydroxylation. Our results show that the induction of P450-IIEI protein in hamsters by ethanol and pyrazole, an "ethanol-like" inducer, is accompanied by an increase in translatable P450-IIEI mRNA.

Animals↗
PubMed1988

Blood markers of alcoholic liver disease.

Not all heavy drinkers develop severe alcoholic liver disease. Genetic factors are probably involved, but no corresponding useful markers have been developed thus far. Of greater practical applicability is the recognition of early changes in the liver that may indicate that the process of scarring or fibrosis has been initiated. Measurement of breakdown products of collagen, the protein of the fibrotic tissue, have been found to be useful for detecting these early stages. Assessment of glutamic dehydrogenase activity in the serum also provides some indication of the degree of inflammation and necrosis present in the liver, but not of the alcohol intake. The severity of the latter can be assessed with a variety of biological markers, to which circulating antibodies against acetaldehyde adducts have recently been added.

Alcoholism↗
PubMed1988

Alterations in synaptic membrane molecular order associated with alcoholization and protein deficiency in rats.

The effects of chronic alcoholization and protein deficiency on synaptic membrane characteristics were studied in rats fed the following four liquid diets for 4 weeks: a protein-deficient diet containing alcohol, a protein-deficient diet containing no alcohol, a non-protein-deficient diet containing alcohol and a non-protein-deficient diet containing no alcohol. A fluorescent probe, diphenylhexatriene (DPH), was used to estimate the fluidity of synaptic membranes and their sensitivity to the fluidizing effect of ethanol added in vitro, in concentrations ranging from 50 mM to 800 mM. Prior to in vitro addition of ethanol, the difference between the fluidity of synaptic membranes of alcoholized and non-alcoholized animals was significant for the two groups of protein-deficient animals but not for the two groups of non-protein-deficient animals. After in vitro addition of ethanol, the differences between the fluidity of synaptic membranes of the alcoholized and non-alcoholized animals were larger and more frequently significant for the protein-deficient animals than for the non-protein-deficient animals. In view of previous observations that rats fed a protein-deficient diet experience more severe withdrawal symptoms following alcoholization than rats fed a nutritionally adequate diet, the results of the present experiment lend additional support to the hypothesis that tolerance and dependence may be mediated by alterations in biomembrane characteristics.

Alcoholism↗
PubMed1988

Combined effects of protein deficiency and chronic ethanol consumption on rat pancreas.

This study was performed in order to delineate the combined effects of protein deficiency and chronic ethanol ingestion on the rat pancreas. Rats fed ethanol in combination with protein-deficient diets developed marked steatosis, whereas alcohol ingestion with nutritionally adequate diets and protein deficiency alone each were associated with a more moderate degree of pancreatic lipid accumulation. On biochemical analysis, it was found that protein deficiency decreased pancreatic phospholipid content. Furthermore, both protein deficiency and chronic ethanol consumption increased pancreatic cholesteryl ester content, and their effects were additive. Functional changes were studied using isolated pancreative acini. Protein deficiency depressed the tissue content of lipase and the ability of pancreatic acini to secrete lipase. Chronic ethanol feeding increased lipase levels in the acini and also their secretory capacity. Thus, to the extent that enzyme accumulation in the pancreas plays a role in the pathogenesis of alcoholic pancreatitis, these results may explain the higher incidence of pancreatitis in well-nourished alcoholics that has been documented in dietary surveys.

Alcoholism↗
PubMed1988

Biphasic control of polymorphonuclear cell migration by Kupffer cells. Effect of exposure to metabolic products of ethanol.

In order to investigate the role of the Kupffer cells in the regulation of the inflammatory reaction seen in alcoholic hepatitis, rat liver Kupffer cells were cultured and exposed to products of ethanol metabolism. The resultant supernatants were tested to study their ability to stimulate or inhibit polymorphonuclear cell chemotaxis. Kupffer cells produced increased chemokinetic activity for human polymorphonuclear leukocytes (84 +/- 6 vs. 61 +/- 4 randomly migrating cells per 5 high power fields; p less than 0.01); when incubated with soluble products of microsomal peroxidation, the Kupffer cells engendered more chemokinetic activity than that produced by untreated Kupffer cells (106 +/- 6 vs. 84 +/- 6 cells per 5 high power fields; p less than 0.05). When Kupffer cells were incubated with acetaldehyde, the chemokinetic activity that appeared in the supernatant did not differ from control (51 +/- 3 vs. 61 +/- 4 randomly migrating cells per 5 high power fields; p = NS). Chemotaxis of polymorphonuclear cells was not observed when the Kupffer cell supernatants were tested by checkerboard analysis. Kupffer cells released a factor which, at different concentrations, inhibited the response of polymorphonuclear cells to the synthetic polypeptide chemotactic factor f-met-leu-phe by 47% (p less than 0.001). This effect was unchanged when the cells were exposed to acetaldehyde or to soluble products of microsomal peroxidation. Our results demonstrate that Kupffer cells are capable of stimulating or inhibiting polymorphonuclear cell chemotaxis and that some of these effects may be influenced by the products of ethanol metabolism, suggesting that Kupffer cells may play an important role in the regulation of the inflammatory reaction seen in alcoholic hepatitis.

Acetaldehyde↗
PubMed1988

P3 in alcoholics with disordered regulation of aggression.

Alcoholics have been found to show deficits in the P3 component of event-related potentials obtained using information-processing paradigms. However, alcoholic patients form a heterogeneous population. In a study of P3 voltages in subgroups of alcoholics with disorders in mood and aggression control, we observed significant decrements in these voltages in patients with lifelong histories of aggressive behavior. Patients with histories of incarceration for crimes involving physical violence had the lowest P3 amplitudes. The same patients also had a rate of paternal alcoholism significantly higher than that observed in the rest of the population. They could thus be classified as type 2 alcoholics, as a tendency to antisocial behavior and a high genetic loading for alcoholism have been described in this alcoholic subtype. These data could indicate that decrements in P3 amplitude characterize a subgroup of alcoholics with a disordered regulation of aggression. Alternatively, P3 deficits could be associated with some psychopathological conditions in individuals who abuse alcohol rather than with alcoholism, per se.

Adult↗
PubMed1988

Desmin distinguishes cultured fat-storing cells from myofibroblasts, smooth muscle cells and fibroblasts in the rat.

To differentiate cultured rat liver myofibroblasts, fat-storing cells, aortic smooth muscle cells and skin fibroblasts from each other, desmin and vimentin stainings were undertaken by indirect immunofluorescence using monoclonal antibodies. In myofibroblasts, the reaction with antibodies to vimentin was positive but that with antibodies to desmin was virtually negative. In primary cultures as well as subsequent passage of fat-storing cells, reactions with antibodies to both desmin and vimentin were positive. In primary culture of smooth muscle cells, both reactions were positive, but in the first passage, smooth muscle cells lost the reactivity with antibodies to desmin. Fibroblasts showed a positive reaction with antibodies to vimentin and a negative one with antibodies to desmin. Thus, immunohistochemistry of intermediate filaments allows for the differentiation between fat-storing cells, which are desmin- and vimentin-positive, and myofibroblasts or fibroblasts, which are desmin-negative but vimentin-positive. Smooth muscle cells are also vimentin-positive and become desmin-negative after the first passage.

Adipose Tissue↗
PubMed1988

The microsomal ethanol oxidizing system: its role in ethanol and xenobiotic metabolism.

After chronic ethanol consumption, the activity of the microsomal ethanol-oxidizing system (MEOS) increases and contributes to ethanol tolerance, as most conclusively shown in alcohol-dehydrogenase-negative deermice. In man and animals, there is an associated rise in microsomal cytochrome P-450, including a specific form (P-450IIEI) with high affinity for ethanol and for the activation of some drugs (i.e. acetaminophen), carcinogens (i.e. N-nitrosodimethylamine) and hepatotoxic agents (i.e. CCl4), thereby contributing to the susceptibility of alcoholics to xenobiotics, including industrial solvents. In addition, a benzoflavone-inducible liver cytochrome P-450 isoenzyme distinct but catalytically similar to cytochrome P-450IIE1 was purified which may play a significant role in drinkers who also are heavy smokers. Cross-induction of other microsomal enzymes is associated with enhanced metabolism of various drugs, resulting in drug tolerance. Catabolism of retinol was also found to be accelerated, in part through activation of newly discovered vitamin A depletion and possibly toxicity. Thus, elucidation of the microsomal metabolism of ethanol explains a number of complications that develop in alcoholics.

Amino Acid Sequence↗
PubMed1988

Metabolic effects of acetaldehyde.

Acetaldehyde, the toxic product of ethanol metabolism in the liver, covalently binds to a variety of proteins, thereby altering liver function and structure. Through its binding to tubulin, acetaldehyde decreases the polymerization of microtubules thereby impairing protein secretion and favouring their retention, with associated swelling of hepatocytes. Acetaldehyde adduct formation also impairs some enzyme activities. Either directly or through binding with GSH, acetaldehyde favours lipid peroxidation. Various mitochondrial functions are altered, particularly after chronic ethanol consumption which sensitizes the mitochondria to the toxic effects of acetaldehyde. In cultured myofibroblasts, acetaldehyde stimulates collagen production. The acetaldehyde-protein adducts stimulate the production of antibodies directed against the acetaldehyde epitope. This immune response may contribute to the aggravation or perpetuation of alcohol-induced liver damage. Some acetaldehyde effects, however, could conceivably be considered as beneficial, such as the stimulation of vascular prostacyclin release which may take part in the 'protective' effect of moderate ethanol consumption against some cardiovascular complications.

Acetaldehyde↗
PubMed1988

Vitamin A treatment of sexual dysfunction in male alcoholics.

Thirty abstinent male alcoholics with sexual dysfunction were randomized to treatment with 3 mg RE (10,000 IU) vitamin A or placebo daily for 4 mo. Age, drinking history, period of abstinence before enrollment, and base-line laboratory indices were comparable in both groups at entry. Of the 15 subjects given placebo, 13 had a partial or full recovery of sexual functioning. By contrast, of those given vitamin A, 10 had a partial response. There were no complete responders. Six subjects (1 placebo, 5 vitamin A) who developed liver abnormalities during treatment underwent liver biopsies; five had fibrosis or cirrhosis. A significant decrease in luteinizing hormone was noted in the group given vitamin A compared with the placebo-treated group. Thus vitamin A therapy did not improve sexual functioning in male alcoholics and may have been associated with toxicity.

Alcoholism↗
PubMed1988

In vitro and in vivo inhibitory effect of ethanol and acetaldehyde on O6-methylguanine transferase.

Human and rat O6-methylguanine transferase (O6MeGT) are inhibited in vitro by ethanol at concentrations of 10 to 50 mM and by acetaldehyde, the first metabolite of ethanol, at concentrations as low as 0.01 microM. Several other enzymes, including glyceraldehyde-3-phosphate dehydrogenase and yeast alcohol dehydrogenase, which like O6MeGT have cysteines in their active sites, were not inhibited by acetaldehyde at the levels that inhibited O6MeGT. Disulfiram, an acetaldehyde dehydrogenase inhibitor, enhanced the inhibitory effect of ethanol in vivo. These results indicate that the inhibitory effect of ethanol on O6MeGT activity is mediated primarily via its metabolite, acetaldehyde.

Acetaldehyde↗
PubMed1988

Differential effects of retinoids and chronic ethanol consumption on membranes in rats.

Liver plasma membranes (LPM) were prepared from vitamin A-deficient and -sufficient rats as well as from animals treated with retinoic acid, with or without ethanol. Although the fluorescence polarization value of LPM prepared from retinoic acid-fed animals was significantly lower than that of controls (0.201 +/- 0.008 vs. 0.254 +/- 0.005, P less than 0.001), no effect was seen with a vitamin A-deficient diet (0.259 +/- 0.005). No change in the fluorescence polarization was observed in erythrocyte ghost membranes with either vitamin A deficiency or chronic ethanol consumption. The sialic acid concentration of the membranes was significantly higher in LPM and erythrocyte ghosts obtained from vitamin A-deficient animals (37.6 +/- 1.1 vs. 29.6 +/- 0.7 nmol/mg protein for LPM, P less than 0.01, and 77.7 +/- 0.6 vs. 62.0 +/- 1.7 for erythrocyte ghosts, P less than 0.001); the LPM of retinoic acid-treated animals had the lowest values (26.9 +/- 1.6 nmol/mg protein). This sialic acid concentration of LPM was positively correlated with the fluorescence polarization (r = 0.775, P less than 0.001). Chronic ethanol feeding resulted in lower hepatic and LPM vitamin A and greater LPM fluidity with higher cholesterol esters in all diet groups (P less than 0.001). Because increased sialic acid concentration has been incriminated in the pathogenesis of tumor development, it may provide a mechanism whereby lowered hepatic vitamin A promotes carcinogenesis and retinoic acid feeding opposes this process.

Alcoholism↗
PubMed1988

Increase in tryptophan oxygenase activity in alcoholic patients.

This study was conducted in order to assess whether chronic excessive alcohol consumption affects the activity of the liver enzyme tryptophan oxygenase which is rate limiting along the most important pathway of tryptophan catabolism. Five alcoholics were studied twice, once shortly after admission to an inpatient unit and the second time 1 month later. On each study day patients were given a tryptophan load of 50 mg/kg. Kynurenine in the urines (which reflects tryptophan oxygenase activity) was measured for a period of 6 hr following the load and showed a significantly enhanced activity of the enzyme shortly after cessation of drinking. This increased activity could explain the lowered tryptophan levels we have previously reported in alcoholics. The increase in enzyme activity may have been mediated by a rise in glucocorticoid hormones. In all instances, plasma cortisol measured hourly for 6 hr after the start of the experiment, was higher shortly after cessation of drinking than 1 month later.

Adult↗