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Biomedical subjects

C S Lieber

Publications and source records attributed to C S Lieber.

At least 91 records · Page 5Linked to original sources
PubMed1996

Ethnic differences in gastric sigma-alcohol dehydrogenase activity and ethanol first-pass metabolism.

We assessed whether the low sigma-alcohol dehydrogenase (ADH) activity in Japanese (compared with Caucasians) affects the first-pass metabolism of ethanol. ADH isozyme activities were determined in endoscopic biopsies of the gastric corpus from 24 Japanese and 41 Caucasian men by starch gel electrophoresis and by comparing the reduction of m-nitrobenzaldehyde (a preferred substrate of sigma-ADH) with that of acetaldehyde (a preferred substrate of gamma-ADH) and the glutathione-dependent formaldehyde oxidation (a specific reaction of chi-ADH). Alcohol pharmacokinetics was compared in 10 Japanese and 10 Caucasians after administration of ethanol (300 mg/kg of body weight) intravenously or orally, using 5 and 40% oral solutions. Japanese exhibited lower sigma-ADH activity than Caucasians, with no difference in the other gastric isozymes. With 5% ethanol, first-pass metabolism was strikingly lower in Japanese than in Caucasians. Blood alcohol levels were similar because of the high elimination rate in Japanese due to the hepatic beta 2-ADH variant. With 40% ethanol, the first-pass metabolism increased in both groups to comparable levels, suggesting an additional contribution by chi-ADH at high ethanol concentrations. These results indicate that sigma-ADH activity contributes significantly to gastric ethanol oxidation and its lower activity in Japanese is associated with lesser first-pass metabolism.

Alcohol Dehydrogenase↗
PubMed1996

Alcoholism is associated with hepatitis C but not hepatitis B in an urban population.

OBJECTIVES: Previous studies have suggested an association of viral hepatitis with alcoholism, although the role of confounding risk factors (e.g. i.v. drug use) has not been adequately excluded. We therefore compared the seroprevalences of hepatitis B and C in alcoholic patients to that of a nonalcoholic control group. METHODS: Hepatitis B surface antigen, hepatitis B core antibody, hepatitis B surface antibody, and hepatitis C virus antibody testing (second generation ELISA and a confirmatory recombinant immunoblot assay) was performed in 150 consecutive alcoholics admitted for detoxification and in 166 randomly selected patients attending a general medical clinic who were screened for alcoholism. RESULTS: Hepatitis B and C seropositivities in actively drinking alcoholics are 49.3 and 35.3%, respectively, and were significantly associated with a history of i.v. drug abuse. Out of 166 general medicine clinics patients, 93 were classified as nonalcoholic (by both self-report and collateral verification), 46 patients had a history of alcoholism , and 27 were indeterminate. In the subgroup of patients without known viral hepatitis risk factors, there was no significant difference in hepatitis B seropositivity among nonalcoholic general medicine clinic patients, alcoholic general medicine clinic patients, and alcoholic patients admitted for detoxification (22.1%, 30.3%, and 27.6%, respectively). In contrast, anti-HCV recombinant immunoblot assay seropositivity in alcohol patients admitted for detoxification without risk factors was significantly greater than in nonalcoholic general medicine patients without risk factors (10 vs 0%, p >0.01). Stepwise logistic regression analysis revealed that alcoholism requiring detoxification was a significant risk factor for hepatitis C but not for hepatitis B seropositivity. CONCLUSIONS: The increased seroprevalence of hepatitis C in actively drinking alcoholic patients without known risk factors suggests that alcoholism, in some way, is a predisposing factor for HCV infection.

Aged↗
PubMed1995

Upstream structure of human ADH7 gene and the organ distribution of its expression.

The ADH7 gene encoding human class IV (sigma) alcohol dehydrogenase (ADH) was cloned from a Caucasian genomic DNA library and its upstream structure was determined. Moreover, the organ distribution of its expression was examined. Northern hybridization analysis with a specific probe for sigma-ADH showed that expression of the gene is organ specific rather than ubiquitous, and occurs in the stomach but not in the liver. The lack of CG rich sequence and presence of TATA and CCAAT boxes in the upstream region of ADH7 may reflect the organ specific expression. The findings that this region lacks hepatocyte nuclear factor and has only one CCAAT enhancer binding protein consensus site may account for the fact that this gene is not expressed in the liver. The upstream region had sequences which are compatible with a glucocorticoid response element, a metal binding factor-1, and an active gene regulatory protein-1, suggesting that sex hormones, zinc, and retinoic acid may be involved in the regulation of the expression of this gene.

Alcohol Dehydrogenase↗
PubMed1995

Comparison of the ADH7 gene structure in Caucasian and Japanese subjects.

The ADH 7 gene, encoding the sigma-alcohol dehydrogenase isozyme, was cloned from a Caucasian genomic DNA library. Comparison of the nucleotide sequence of its exon 7 with that of an ADH 7 previously cloned from a Japanese subject revealed a substitution of the glycine-287 in the Caucasian sigma isozyme with valine in the Japanese. Since a possible mutation at this site could account for ethnic differences in the gastric activity of this isozyme, the frequency of this change was examined in both races. The exon 7 of the ADH 7 was amplified by PCR from 7 Caucasian and 7 Japanese genomic DNA and applied to restriction fragment length polymorphism analysis, using Ava II to digest the sequence encoding glycine-287 and Mae III to digest that encoding valine-287. Regardless of ethnicity, all PCR amplicons were digested by Ava II and none by Mae III, suggesting that the ethnic difference in the 287 amino acid may represent an uncommon mutation, which does not account for the high frequency of minimal activity of the sigma-alcohol dehydrogenase in the Japanese stomach compared to those of non-Orientals.

Alcohol Dehydrogenase↗
PubMed1995

First-pass metabolism of alcohol. Absence of diurnal variation and its inhibition by cimetidine after evening meal.

To determine whether the first-pass metabolism (FPM) of orally consumed alcohol varies with the time of day, 12 healthy male subjects were tested with both oral and intravenous alcohol (0.3 g/kg), in the morning and evening, always 1 hr after the same standard meal. The results revealed no significant differences in FPM (81.6 +/- 11.6 vs 92.8 +/- 10.6 mg/kg) or in any other index of alcohol absorption and metabolism. Eleven subjects were also tested in the evening after treatment with cimetidine, an H2-antagonist that inhibits gastric alcohol dehydrogenase activity in vitro. Compared to baseline, cimetidine (1 g/day for eight days) significantly decreased FPM (from 100.1 +/- 8.0 to 52.6 +/- 11.4 mg/kg, P < 0.01) and increased the systemic bioavailability of alcohol (from 66 +/- 3 to 82 +/- 4%, P < 0.01), as well as peak blood alcohol concentrations (from 4.3 +/- 0.4 to 5.9 +/- 0.5 mM, P < 0.05) and areas under the curve (from 5.1 +/- 0.5 to 7.0 +/- 0.5 mM/hr, P < 0.01). The results indicate the absence of diurnal variation in FPM and suggest that patients given cimetidine should be warned of its possible interaction with alcohol regardless of the time of day.

Administration, Oral↗
PubMed1995

Gastric metabolism of ethanol in Syrian golden hamster.

First-pass metabolism (FPM) of orally ingested alcohol has been attributed to gastric alcohol dehydrogenase (ADH) activity in both humans and rats. To determine whether gastric alcohol dehydrogenase is essential for alcohol FPM, we sought a species lacking this enzyme. We found that Syrian golden hamsters have negligible gastric ADH yet alcohol FPM (265 +/- 25 mg ethanol/kg) was comparable to that of rats (251 +/- 31 mg/kg). To determine whether hamster gastric mucosal cells metabolize sufficient alcohol to account for this FPM, primary cultures were established, and these cells metabolized 1.99 +/- 0.84 mumol ethanol/10(6) cells/hr, an amount sufficient to account for the bulk of alcohol FPM. In contrast to alcohol dehydrogenase, catalase activity in hamster gastric mucosa (870 +/- 93 units/g tissue) was eightfold higher than in rat gastric mucosa (111 +/- 9 units/g tissue; P < 0.0001). FPM in hamsters treated with 3-aminotriazole was reduced from 242 +/- 24 to 130 +/- 22 mg/kg (P < 0.05) but was not reduced in rats. The results imply that catalase participates in gastric alcohol metabolism of hamsters.

Alcohol Dehydrogenase↗
PubMed1995

The effect of chronic alcohol administration on cerulein-induced pancreatitis.

Alcohol consumption i associated with pancreatitis, but the mechanism underlying this injury remains unclear. Alcohol consumption has recently been shown to increase the fragility of both rat pancreatic lysosomes and zymogen granules in vitro, which may predispose to autodigestion via the intracellular activation of digestive enzymes by lysosomal enzymes. Cerulein-induced pancreatitis is also associated with lysosomal fragility. To determine the effect of alcohol consumption on this form of pancreatic injury, the severity of pancreatitis was compared in three groups of rats following i.v. cerulein infusion: rats fed alcohol in a liquid diet, pair-fed dextrose controls, and chow-fed controls. The histological severity of pancreatitis induced by supramaximal cerulein infusion was not found to be increased by prior alcohol consumption. Since alcohol did not appear to increase the severity of pancreatic injury induced by cerulein, we sought to define biochemical parameters that might precede obvious injury. The subcellular distribution of cathepsin B activity and markers of lysosomal fragility were compared in the same groups of experimental animals. Cerulein infusion led to a marked redistribution of cathepsin B activity from the lysosomal to the zymogen-granule-enriched fractions.For animals killed in the fed state, a redistribution of cathepsin B activity toward the zymogen-granule-enriched fraction was also demonstrated in alcohol-fed animals compared to their pair-fed controls. However, chronic alcohol administration did not influence the effect of cerulein on subcellular cathepsin B distribution or lysosomal fragility. In this rat study, administration of alcohol did not increase the effects of supramaximal doses of cerulein on the pancreas.

Amylases↗
PubMed1995

Metabolism of ethanol in rat gastric cells and its inhibition by cimetidine.

BACKGROUND/AIMS: Several studies have shown that the stomach has sufficient alcohol dehydrogenase activity to metabolize a significant amount of alcohol and that cimetidine depresses this alcohol dehydrogenase activity. However, both gastric metabolism of ethanol and its inhibition by cimetidine remain controversial. Given the difficulty in assessing gastric metabolism of ethanol in vivo, this subject was investigated in vitro. METHODS: Cultured rat gastric epithelial cells were incubated with 200 mmol/L [1-14C]ethanol for 90 minutes with and without cimetidine (0.1-1 mmol/L) or omeprazole (1 mmol/L). The quantity of ethanol oxidized by gastric cells was measured by the amount of acetate produced using ion exchange chromatography. RESULTS: The majority of cells at confluency had typical features of mucous cells. The gastric cells metabolized significant amounts of ethanol, sufficient to account for in vivo first-pass metabolism of ethanol in rats. Cimetidine, but not omeprazole, reduced ethanol metabolism by 39.9% +/- 4.9% (P < 0.01), an inhibition comparable with that previously reported for first-pass metabolism in vivo. CONCLUSIONS: Gastric cells in tissue culture are capable of significant ethanol oxidation, the in vitro rates are sufficient to account for first-pass metabolism of ethanol in vivo, and cimetidine inhibits ethanol metabolism in tissue culture, an effect that parallels its decrease of first-pass metabolism in vivo.

Alcohol Dehydrogenase↗
PubMed1995

Carotenoids and tocopherols in various hepatobiliary conditions.

BACKGROUND: Previous studies revealed hepatic interactions of beta-carotene with alcohol in non-human primates, but bile carotenoids and alpha-tocopherol have not previously been explored in man. METHODS: To compare the plasma and biliary concentrations of carotenoids, retinoids and tocopherols among controls and patients with biliary and pancreatic diseases, these compounds were measured by high performance liquid chromatography in bile collected during 41 endoscopic retrograde cholangiopancreatographies. RESULTS: In 14 subjects with normal endoscopic retrograde cholangiopancreatography (controls), bile contained beta-carotene, alpha-carotene, lycopene, cryptoxanthin, lutein+zeaxanthin (23.9 +/- 6.6, 3.9 +/- 1.1, 39.9 +/- 21.6, 22.5 +/- 4.6, 217.1 +/- 27.8 nmol/l, respectively) with corresponding plasma values of 399.7 +/- 72.6, 88.5 +/- 18.8, 588.2 +/- 75.0, 145.1 +/- 25.9, 319.3 +/- 33.7 nmol/l. In 13 patients in whom bile duct stones impaired biliary excretion (as reflected by raised serum bilirubin), beta-carotene was significantly decreased in both plasma (199.6 +/- 35.5 nmol/l) and bile (9.4 +/- 2.0 nmol/l), with a similar trend for other carotenoids. The beta-carotene plasma/bile ratio was maintained, as well as a correlation between the two (r = 0.56; p = 0.048). Furthermore, in three subjects with complete biliary obstruction, plasma beta-carotene (35.8 +/- 20.2 nmol/l) decreased even more, probably reflecting malabsorption. In 11 patients with pancreatic diseases, plasma and bile beta-carotene were 107.9 +/- 17.8 and 6.6 +/- 2.0 nmol/l respectively, while a correlation between the two (r = 0.70; p = 0.018) again persisted, confirming the role of plasma beta-carotene in determining bile concentrations. Indeed, for the entire group (n = 41), the correlation between plasma and bile or red blood cell beta-carotene was highly significant, whereas plasma/red blood cell ratios remained unchanged. Similar findings were observed for alpha-tocopherol, with 8.4 +/- 0.9 mumol/l in control bile (vs. 23.2 +/- 1.7 mumol/l in plasma), and no significant change in the various groups. CONCLUSIONS: 1) Carotenoids and tocopherols undergo biliary excretion in man. 2) Biliary concentrations reflect plasma levels in both normal and pathologic states. 3) Decreased biliary excretion of carotenoids does not increase plasma concentrations.

Adult↗
PubMed1995

Significant increase of blood alcohol by cimetidine after repetitive drinking of small alcohol doses.

To assess effects of repetitive alcohol drinking and pre-existing first-pass metabolism on the cimetidine-induced increase in blood alcohol concentrations, 20 healthy men (aged 20 to 40) of varied ethnicity and consuming less than 60 g alcohol per week underwent baseline quantitation of first-pass metabolism of alcohol. This was followed by oral administration of 0.6 g/kg ethanol given postprandially in 3 to 4 drinks spread over 135 min, before and after cimetidine (400 mg twice a day for 7 days). Blood alcohol concentrations were determined by breath analysis. First-pass metabolism was quantified by applying Michaelis-Menten kinetics to blood alcohol curves after intravenous or oral administration of equal alcohol doses. At baseline, 15 subjects had a substantial first-pass metabolism (over one sixth of the dose); their alcohol levels increased with repeated doses with a mean peak of 27 +/- 3 mg/dl before and 39 +/- 5 after cimetidine (P < 0.01), an effect much greater and longer than after a single alcohol dose. Three subjects exceeded 50 mg/dl, the legal limit for driving in several countries. By contrast, in the five subjects with minimal first-pass metabolism, cimetidine did not increase alcohol levels. Thus, under conditions mimicking social drinking, cimetidine increased blood alcohol to concentrations known to impair psychomotor skills and they persisted at those levels over prolonged periods of time. In a minority of subjects, no such interaction was found, but their first-pass metabolism at baseline was absent or minimal and thus no inhibition by the drug was to be expected.

Adult↗
PubMed1995

Utility of carbohydrate-deficient transferrin as a marker of relapse in alcoholic patients.

Carbohydrate-deficient transferrin (CDT) has been proposed as a marker of alcoholism. However, its role in monitoring alcoholic patients for relapse has not been extensively studied. We therefore performed sequential serum CDT measurements using a microcolumn/radioimmunoassay method (Kabi Pharmacia, Piscataway, NJ) in 86 male alcoholics participating in a hepatitis vaccination program who were monitored for relapse using self-report and collateral history (when available). The maximum serum CDT was significantly higher in patients who relapsed (n = 38) (33.1 +/- 3.1 mg/liter), as compared with abstinent subjects with collateral verification (n = 39) (18.8 +/- 1.3, p < 0.001) and abstinent patients without collateral verification (n = 9) (17.4 +/- 1.3, p < 0.01). Using the manufacturer's currently recommended threshold of 20 mg/liter for males, serum CDT was elevated in 29 of 38 patients who relapsed (sensitivity 76.3%). In 16 (42.1%) of the relapsed patients, a serum CDT above this threshold preceded the patient's self-report by at least 28 days. However, serum CDT exceeded 20 mg/liter in 10 of 48 patients who remained sober (specificity 79.2%); three of these patients had clinical and/or pathological evidence of cirrhosis. Using a threshold of 25 mg/liter, 21 of 38 patients who relapsed had an elevated serum CDT (sensitivity 55.3%); 12 (31.6%) of these patients had elevated serum CDT before self-report. Only 4 of 48 subjects who remained sober had serum CDT levels that exceeded 25 mg/liter (specificity 91.7%); three of these patients had clinical and/or pathological evidence of cirrhosis. In conclusion, serial serum CDT testing detects relapses before self-report in male subjects. Values between 20-25 mg/liter suggest relapse, but call for collateral verification, whereas CDT values above 25 mg/liter are usually diagnostic of relapse in the absence of cirrhosis.

Alcoholism↗
PubMed1995

Serum carbohydrate-deficient transferrin: mechanism of increase after chronic alcohol intake.

Carbohydrate-deficient transferrin (CDT) is now considered to be the most sensitive and specific biological marker of alcohol abuse. However, the mechanism by which chronic alcohol consumption causes an elevation of CDT levels in serum is still not understood. Therefore, we fed eight pairs of male rats a nutritionally adequate liquid diet containing either alcohol (36% of energy) or isocaloric dextrose (control) for 4 weeks, after which blood and liver samples were obtained. Serum CDT content in alcohol-treated rats increased by 45% (P < .05) in ethanol-fed animals compared with their corresponding controls. In contrast, in rats fed ethanol, the activities of sialyltransferase (ST), galactosyltransferase (GT), and N-acetylglucosamine transferase (N-AGT), which are glycosyltransferases involved in transferrin carbohydrate side chain synthesis, were diminished by 24% and 40% (P < .05), 23% and 51% (P < .05, .001), and 20% and 26% (P < .05) in total liver homogenates and Golgi fraction (GF) 1, respectively, when expressed as units/100 g body weight. These enzymes were also significantly less active in hepatic GFs 2 and 3. The depression of the transferase activities in ethanol-fed rats appeared to be due, at least in part, to enzyme inactivation by acetaldehyde, whereas ethanol itself was without effect. Similar results were obtained in humans: five alcohol abusers were found to exhibit a 23% decrease in hepatic sialyltransferase and a 41% increase in sialidase activities, respectively, when compared with three nondrinking subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholism↗
PubMed1995

Carotenoid, retinoid and vitamin E status of the oropharyngeal mucosa in the alcoholic.

Concentrations of carotenoids, retinoids and tocopherols were determined in the homogenate of macroscopically normal appearing oropharyngeal mucosa from 10 chronic alcoholics and from 11 control patients. All the alcoholics except one had oropharyngeal cancer. No significant difference was found in tissue levels of carotenoids and tocopherols between alcoholics and controls. Furthermore, in seven of 11 controls, retinol was undetectable in the oropharyngeal mucosa, while in the alcoholics only two out of 10 had unmeasurable retinol levels. These results do not support the concept that ethanol-associated oropharyngeal carcinogenesis is due, at least in part, to local deficiencies in retinoids, carotenoids or alpha-tocopherols.

Adult↗
PubMed1994

Molecular cloning of human class IV alcohol dehydrogenase cDNA.

A cDNA encoding a new type of alcohol dehydrogenase was cloned from a human stomach cDNA library. PCR amplification of 5'-stretch human stomach lambda gt11 library, using degenerate inosine-containing oligonucleotide probes compatible with peptide sequences of human sigma-ADH, resulted in a single product. Subsequently, internal non-degenerate primers were constructed according to the sequences occurring in the product. By PCR with combinations of these new primers and lambda gt11 forward and reverse primers, fragments of the cDNA containing its 5' and 3' ends were amplified. The full length cDNA sequence has 1125 nucleotides with a 72% similarity to those of human class I ADH. The polypeptide sequence, predicted from the cDNA, corresponds to 373 amino acids with a high degree of similarity (96%) to fragments of sigma-ADH previously reported. Northern hybridization analysis with the specific probe for the mRNA of this protein showed that it is expressed in the human stomach but not in the liver. These data indicate that the cDNA we cloned is that of human class IV ADH.

Alcohol Dehydrogenase↗
PubMed1994

Alcohol and the liver: 1994 update.

This article reviews current concepts on the pathogenesis and treatment of alcoholic liver disease. It has been known that the hepatotoxicity of ethanol results from alcohol dehydrogenase-mediated excessive generation of hepatic nicotinamide adenine dinucleotide, reduced form, and acetaldehyde. It is now recognized that acetaldehyde is also produced by an accessory (but inducible) microsomal pathway that additionally generates oxygen radicals and activates many xenobiotics to toxic metabolites, thereby explaining the increased vulnerability of heavy drinkers to industrial solvents, anesthetics, commonly used drugs, over-the-counter medications, and carcinogens. The contribution of gastric alcohol dehydrogenase to the first-pass metabolism of ethanol and alcohol-drug interactions is discussed. Roles for hepatitis C, cytokines, sex, genetics, and age are now emerging. Alcohol also alters the degradation of key nutrients, thereby promoting deficiencies as well as toxic interactions with vitamin A and beta carotene. Conversely, nutritional deficits may affect the toxicity of ethanol and acetaldehyde, as illustrated by the depletion in glutathione, ameliorated by S-adenosyl-L-methionine. Other "supernutrients" include polyunsaturated lecithin, shown to correct the alcohol-induced hepatic phosphatidylcholine depletion and to prevent alcoholic cirrhosis in nonhuman primates. Thus, a better understanding of the pathology induced by ethanol is now generating improved prospects for therapy.

Animals↗