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Biomedical subjects

C S Lieber

Publications and source records attributed to C S Lieber.

At least 271 records · Page 15Linked to original sources
PubMed1986

Interaction between ethanol metabolism and mixed-function oxidation in alcohol dehydrogenase positive and negative deermice.

To assess the effect of non alcohol dehydrogenase (ADH) ethanol metabolism on mixed-function oxidation, aminopyrine demethylation was studied in vivo and in vitro in deermice having normal liver ADH (ADH+) or lacking it (ADH-), in the presence and absence of ethanol. When injected 15 min prior to administration of [14C]aminopyrine, ethanol reduced the 14CO2 exhalation rate in both ADH- and ADH+ deermice. The inhibitory effect of ethanol was dose dependent in both strains, and there was no significant difference between strains. Chronic ethanol feeding increased 14CO2 production from [14C]aminopyrine in both animal strains (ADH- alcohol 5.9 +/- 1.3 vs ADH- control 2.9 +/- 0.03, P less than 0.025; ADH+ alcohol 5.9 +/- 0.3 vs ADH+ control 2.7 +/- 1.3 nmoles aminopyrine/100 g body wt/min, P less than 0.001). Alcohol feeding also induced aminopyrine N-demethylase activity measured in vitro. This induction was more pronounced in ADH- deermice. Ethanol also inhibited aminopyrine demethylation in liver homogenates from ADH- and ADH+ animals in a dose-dependent manner and to a comparable degree in both strains. The kinetics of aminopyrine N-demethylase inhibition by ethanol was competitive in the microsomal fraction from ADH- as well as ADH+ animals. These results suggest that inhibition of mixed-function oxidation by ethanol may be due to an effect of ethanol on the hepatic microsomes rather than to redox changes produced by ADH-mediated ethanol oxidation. Further, chronic ethanol feeding increased microsomal aminopyrine demethylation independently of the presence of ADH.

Alcohol Dehydrogenase↗
PubMed1986

Lymphocyte subpopulations in patients with alcoholic liver disease.

To determine whether abnormalities of the lymphocyte populations are associated with alcoholic liver disease, we have characterized the subpopulations of lymphocytes in 30 alcoholic patients with and without liver disease. Total T lymphocytes were decreased in patients with alcoholic hepatitis and alcoholic cirrhosis. However, T4 (helper) and T8 (suppressor/cytotoxic) cells and the T4 and T8 cell ratio were similar to the values in controls. In these patients, the sums of T4/T8 cells exceeded that of total T cells, an alteration apparently related to severe liver damage. Cells reacting with antisera to immunoglobulins (B lymphocytes) and to Dr determinants were also within the normal range. In contrast, NK/K (natural killer/killer) cells were increased in the group of patients with steatosis or without liver alteration. Increase of NK/K cells was not observed in patients who were abstinent from alcohol for a period of two weeks or more, suggesting that alcohol may have been responsible for the increase in this lymphocyte population.

Adult↗
PubMed1986

Role of intestinal bacterial overgrowth in ethanol production and metabolism in rats.

To investigate the role of intestinal bacterial overgrowth on the production and metabolism of ethanol, rats with a jejunal self-filling diverticulum (blind-loop) were compared to controls with a self-emptying diverticulum. Both endogenous ethanol and acetaldehyde were found in the blind-loop contents. Intragastric administration of sucrose produced a marked increase in acetaldehyde and acetate in the portal venous blood, with only a modest elevation of ethanol. Blind-loop contents readily oxidized ethanol to acetaldehyde in a concentration-dependent manner and more actively under aerobic than anaerobic conditions. This oxidation was inhibited by antibiotics and was reproduced with isolated microorganisms. Intragastric administration of ethanol to rats with blind-loops markedly increased acetaldehyde and acetate concentrations in the portal vein and, to a lesser extent, in the systemic blood, compared with the controls. By contrast, both portal and systemic blood ethanol concentrations were lower in the rats with a blind-loop compared with controls, even though the amounts of ethanol retained in the digestive tract were similar. A dose of ethanol about twice as large as in controls was required to produce similar systemic blood levels. Both in rats with a blind-loop and in the controls, the areas under the curve of blood ethanol concentrations were smaller after intragastric than after intravenous ethanol administration (1 g ethanol/kg body wt). This difference was exaggerated in the rats with a blind-loop. Thus, a considerable amount of ethanol is oxidized in the gastrointestinal lumen of rats with a blind-loop. The resulting high concentrations of acetaldehyde, both in the intestinal lumen and the portal blood, may have deleterious effects on the gastrointestinal mucosa and the liver.

Acetaldehyde↗
PubMed1986

Protein deficiency alters rat pancreatic lipid composition.

Pancreatic lipid composition was found to be altered in rats fed a protein-deficient diet for 4 wk. Increases in triglycerides and cholesteryl ester content were found in association with a decrease in phospholipids. Alterations in these lipids may adversely affect membrane function and predispose to pancreatic injury.

Animals↗
PubMed1986

Increased vitamin A in esophagus and other extrahepatic tissues after chronic ethanol consumption in the rat.

In rats fed ethanol (36% of total energy) for 1 month, vitamin A content of the esophageal mucosa was found to be increased 5-fold, compared to animals pair-fed an isocaloric control diet containing the same amount of vitamin A. Similar results were observed with diets of either lower vitamin A content or zinc supplementation. Significant increases of retinoids were also found in lungs, trachea, kidneys, and testes, but not in the eyes. These increases in extrahepatic tissues contrasted strikingly with the concomitant decrease in the liver and suggests that chronic ethanol consumption may be associated with some mobilization of vitamin A from the liver to other organs.

Alcoholism↗
PubMed1986

Oxidation of ethanol to acetaldehyde by bronchopulmonary washings: role of bacteria.

The synergistic effects of tobacco smoking and alcohol consumption on the incidence of upper respiratory cancer may be linked to their common ability to produce acetaldehyde, an irritant and potential mutagen. Since alcohol consumption in most individuals results in very low concentrations of acetaldehyde in the blood, we determined whether bronchopulmonary cellular components are capable of oxidizing ethanol to acetaldehyde. We found that significant production of acetaldehyde occurred in vitro after incubation of human bronchopulmonary washings with 25 mM ethanol. Acetaldehyde production was increased in active smokers and related to microorganisms in the bronchopulmonary tract. It was abolished by preincubation of the washings with antibiotics and was reproduced in vitro with Streptococcus pneumoniae. Normal pulmonary cells in bronchopulmonary washings did not produce acetaldehyde from ethanol.

Acetaldehyde↗
PubMed1986

New technique for the isolation of functional rat pancreatic mitochondria and its application to models of pancreatic injury.

The role of mitochondria in the initiation or promotion of pancreatic pathologic conditions has not been clearly delineated. In this context, it has recently been suggested that abnormal mitochondrial function may account for the fat accumulation observed in pancreatic acinar cells in alcoholism. To study these issues, we developed a method for the isolation of functional mitochondria from the rat pancreas. The resultant mitochondrial pellet possessed oligomycin-insensitive Mg2+-adenosine triphosphatase (ATPase) activity, and coupled respiration could be demonstrated in the presence of EDTA only after Mg2+ had been excluded from the incubation medium. Albumin was also a requirement for the demonstration of coupled respiration in vitro. When this new technique was applied to a rat model of alcohol-induced pancreatic steatosis, no mitochondrial dysfunction was demonstrated, suggesting that some other mechanism is responsible for fat accumulation in pancreatic acinar cells after long-term ethanol consumption. In contrast, DL-ethionine administration to rats produced partial or total uncoupling of mitochondrial respiration in the absence of morphologic evidence of mitochondrial injury.

Adenosine Diphosphate↗
PubMed1986

Humoral immune response to acetaldehyde adducts in alcoholic patients.

Sera of alcoholic patients were found to contain antibodies to acetaldehyde adducts as determined by immunodiffusion. Differences in antibody levels were determined by hemagglutination with acetaldehyde adduct-conjugated red blood cells. Anti-acetaldehyde adduct immunoglobulin titers in 21 healthy, non-drinking individuals ranged from 10-80, whereas 25 of 34 alcoholics had titers of 160 or above (P less than 0.001). Rabbit-polyclonal and mouse-monoclonal antibodies against acetaldehyde adducts did not agglutinate red blood cells of alcoholic patients, indicating that no detectable acetaldehyde-altered epitopes are present on erythrocyte membranes. These results suggest that acetaldehyde-induced immunogenic determinants can initiate a humoral immune response which may differentiate alcoholics from non-alcoholics.

Acetaldehyde↗
PubMed1986

Ultrastructural localization of type III procollagen in baboon liver.

The localization of the extension aminopropeptides of Type III procollagen was studied in baboon liver by the immunoperoxidase method. The aminopropeptides were localized along the collagen fibrils around terminal hepatic venules, in the space of Disse, and in portal tracts of control baboons as well as of alcohol-fed animals. The labeling showed a characteristic periodicity of 60-70 nm, corresponding to the D (67 nm) stagger of collagen fibrils. The data indicate that some extension aminopropeptides of Type III procollagen are not cleaved from procollagen prior to its incorporation into collagen fibrils but that they exist as constituents of mature fibrils.

Animals↗
PubMed1986

Portal fibroblasts and myofibroblasts in baboons after long-term alcohol consumption.

The relative abundance of fibroblasts and myofibroblasts in the portal tracts was assessed in liver biopsy specimens of baboons that developed fatty liver and perivenular fibrosis after alcohol (ethanol) consumption. Fourteen baboons pair-fed with diets containing alcohol, or isocaloric carbohydrate, for up to four years were studied. No fibrosis was observed in the portal tracts of these baboons. The number of mesenchymal cells per 1,000 sq microns of the portal tissue was not changed after alcohol consumption. Electron microscopy demonstrated no increase in the number of fibroblasts, myofibroblasts, or other mesenchymal cells. In view of an increased number of myofibroblasts and fibroblasts in association with the development of perivenular fibrosis as previously reported, the results herein suggest that mesenchymal cells in the portal tracts lack the proper stimuli for proliferation after alcohol consumption.

Alcoholism↗
PubMed1986

Pathogenesis of the hypertriglyceridemia at early stages of alcoholic liver injury in the baboon.

To study the mechanism of alcoholic hypertriglyceridemia, baboons were pair-fed liquid diets containing 50% of energy as ethanol or as additional carbohydrate for 5-16 months. Alcohol-fed animals developed hypertriglyceridemia and early stages of alcoholic injury, namely fatty liver with or without perivenular fibrosis. In the fasting state, the triglyceride content was sixfold higher in very low density (VLDL) and intermediate density (IDL) lipoproteins and twofold higher in low density (LDL) and high density (HDL) lipoproteins. The increase in VLDL was markedly exaggerated in the postprandial state. To investigate the source of these increases, we determined net output or removal of serum triglycerides during circulation through either splanchnic or extrasplanchnic (lower extremities) vascular beds. In the splanchnic territory, there was net output of triglycerides in VLDL and net removal from the other lipoproteins. In alcohol-fed baboons, the output of VLDL-triglycerides into the hepatic (but not into the portal) vein tripled. This increase was mainly due to production of VLDL particles that were larger and had a flotation (Sf greater than 400) different from the Sf 20-400 which predominated in controls. This was associated with increased splanchnic removal of labeled chylomicron- or VLDL-triglycerides. In the lower extremities, there was an arteriovenous difference in VLDL-triglyceride concentration and this was increased in the alcohol-fed animals. Thus, the primary mechanism of the hypertriglyceridemia in alcohol-fed baboons was increased production of large, chylomicron-like VLDL by the liver, whereas both the extrasplanchnic extraction of VLDL-triglycerides and the splanchnic extraction of triglycerides from chylomicron- and VLDL-remnants were secondarily enhanced.

Animals↗
PubMed1985

Bile acids in deermice lacking liver alcohol dehydrogenase.

Liver alcohol dehydrogenase (EC 1.1.1.1) is believed to catalyze the oxidation of 26-hydroxylated intermediates in the biosynthesis of bile acids from cholesterol. We have therefore analyzed the composition and size of the bile acid pool in deer-mice genetically lacking alcohol dehydrogenase. Cholic acid was found to be the major primary bile acid accompanied by small amounts of chenodeoxycholic acid. Variable amounts of secondary bile acids were also present, mainly deoxycholic acid and 3 alpha, 12 alpha-dihydroxy-7-oxo-5 beta-cholanoic acid. The same bile acids were found in animals with normal levels of alcohol dehydrogenase. The pool of bile acids in the gallbladder, small intestine and large intestine varied between 4.2 and 8.4 mumol in four animals lacking alcohol dehydrogenase and between 6.0 and 8.4 mumol in four control animals. Ethanol did not influence pool size or composition of bile acids in the animal studied. It is concluded that alcohol dehydrogenase is not obligatory for normal bile acid biosynthesis.

Alcohol Dehydrogenase↗
PubMed1985

First pass metabolism of ethanol--a gastrointestinal barrier against the systemic toxicity of ethanol.

Both in men and rats, most of the ethanol ingested at a low dose is metabolized before it reaches the systemic circulation. Oxidation of ethanol (mainly in the stomach) accounts for the bulk of this effect. This "first pass" metabolism (FPM) may be viewed as a barrier which protects against the systemic toxicity of ethanol. This barrier can be overcome by large doses of ethanol. Its efficiency is also reduced by a decrease in gastric alcohol dehydrogenase (ADH) activity secondary to chronic alcohol consumption.

Adult↗
PubMed1985

Perivenular fibrosis as precursor lesion of cirrhosis.

Thirty-four male alcoholics underwent sequential liver biopsies as part of their evaluation. Of 19 subjects with simple fatty livers, only three showed progression of liver disease: one developed perivenular fibrosis after two years; a second showed no progression after three years, but developed perivenular fibrosis after four years; the third subject likewise showed no progression after one year, but developed incomplete cirrhosis after six years. In contrast, of 15 subjects with perivenular fibrosis at the time of the initial biopsy, 13 progressed to more severe stages of liver disease during a one- to four-year follow-up interval. Nine developed fibrosis, one developed incomplete cirrhosis and three developed cirrhosis. Thus, patients with perivenular fibrosis at the fatty liver stage are likely to progress to more severe stages of alcoholic liver disease if they continue to consume alcohol.

Adult↗
PubMed1985

Characterization of a major form of rat hepatic microsomal cytochrome P-450 induced by isoniazid.

Cytochrome P-450j has been purified to electrophoretic homogeneity from isoniazid-treated adult male rats; and this enzyme appears to be a major protein induced in hepatic microsomes after administration of isoniazid, as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The hemoprotein has a minimum molecular weight of approximately 51,500, and the ferrous-carbonyl complex of cytochrome P-450j has a Soret maximum at 451-452 nm. The oxidized heme iron appears to be predominately in the high spin state as deduced from the Soret maximum at 395 nm. Ethylisocyanide binds to ferrous cytochrome P-450j to yield spectral maxima at approximately 458 and 430 nm with a resultant 458/430 ratio of 0.7 at pH 7.4. Cytochrome P-450j has no measurable catalytic activity for the metabolism of benzo[a]pyrene (3- and 9-hydroxylation), hexobarbital, testosterone, and 5 alpha-androstane-3 alpha,17 beta-diol-3,17-disulfate. Low, but detectable, catalytic activity is obtained for the metabolism of 7-ethoxycoumarin, benzphetamine, p-nitroanisole, zoxazolamine, and 2-hydroxylation of 17 beta-estradiol. In contrast, cytochrome P-450j effectively catalyzes p-hydroxylation of aniline with a turnover of 12.7 nmol/min/nmol cytochrome P-450j. Hydroxyl radical scavengers, Fe-EDTA, superoxide dismutase, and catalase have no effect on aniline p-hydroxylation catalyzed by cytochrome P-450j. Cytochrome P-450j is distinct from nine other rat hepatic microsomal cytochromes P-450 (P-450a-P-450i) previously purified in this laboratory, as well as different isozymes described by other investigators, based on several parameters including minimum molecular weight, spectral properties, and catalytic activity. In Ouchterlony double diffusion plates, antibodies against cytochromes P-450a-P-450f show no cross-reaction with cytochrome P-450j. Structural differences among cytochromes P-450a-P-450j are apparent from the NH2-terminal sequence of cytochrome P-450j, as well as the electrophoretic profiles of proteolytic digests of the hemoproteins.

Amino Acids↗