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Biomedical subjects

C S Lieber

Publications and source records attributed to C S Lieber.

At least 235 records · Page 13Linked to original sources
PubMed1988

Carbohydrate-deficient transferrin, a marker for chronic alcohol consumption in different ethnic populations.

Serum levels of carbohydrate-deficient transferrin (CDT) were determined in a racially mixed population of 107 alcoholics, 18 healthy, nonalcoholic control subjects, 62 abstinent alcoholics, and in 64 Caucasian patients with various nonalcoholic liver diseases. The upper limit of normal CDT levels was 80 mg/liter (2 SD above the mean). CDT values exceeding this level were found in more than 80% of Black, Puerto Rican, and Caucasian alcoholics who had consumed greater than or equal to 50 g of alcohol/day for 1 month or longer prior to testing. Puerto Rican alcoholics had higher CDT values than the Black and Caucasian ethnic groups; however, these differences were significant only when compared to the Black population. Of 64 patients with nonalcoholic liver diseases, one individual with chronic active hepatitis (CAH) with an alcohol consumption of 20 g/day, and 10 of 26 subjects with primary biliary cirrhoses (PBC), who claimed to consume either no or only occasional moderate amounts of alcohol, had CDT levels ranging from 81 to 144 mg/liter. Seven of these individuals were in advanced stages of PBC. Total transferrin levels were variable and not significantly different in all subject groups studied. CDT/total transferrin ratios were increased in most patients with abnormal amounts of CDT, and there was a significant correlation between these ratios and CDT levels in all study groups. Serum enzyme parameters as well as red blood cell mean corpuscular volumes did not correlate with CDT values.(ABSTRACT TRUNCATED AT 250 WORDS)

Black or African American↗
PubMed1988

Changes in carbohydrate-deficient transferrin levels after alcohol withdrawal.

Sequential serum levels of carbohydrate-deficient transferrin (CDT) were determined in 72 alcoholics at various intervals during detoxification. Before treatment, 57 patients (79%) had increased CDT values (Group A), whereas in 15 individuals (21%) (Group B), CDT levels were within the normal range. In 51 Group A patients, CDT decreased progressively after cessation of alcohol intake (half-life, 16 +/- 5 days), but fluctuated and remained abnormal in the remaining six. Nine Group B patients maintained normal CDT values throughout the follow-up period, but slightly or moderately increased levels were recorded on one occasion in the other six Group B subjects. Patients whose CDT levels had reached normal values after treatment, showed a recurrent increase in CDT after a relapse. gamma-Glutamyl transferase activities, which were elevated in 56% of Group A and in 80% of Group B alcoholics, showed a decrease after cessation of alcohol consumption in most patients with initially elevated values (Group A, 30 of 32; Group B, 10 of 12). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, as well as mean corpuscular volumes (MCV) were normal in the majority of patients. CDT/total transferrin ratios correlated positively with CDT levels. CDT proved to be the most sensitive marker for chronic alcoholism (79%), whereas GGT activity levels were more useful only in patients with normal CDT levels before alcohol withdrawal. In the assessment of treatment outcome, the combination of CDT and GGT as markers yielded a sensitivity of 95%.

Adult↗
PubMed1988

Role of acetone, dietary fat and total energy intake in induction of hepatic microsomal ethanol oxidizing system.

Chronic ethanol consumption results in the induction of a specific hepatic cytochrome P-450 (P450IIE1). However, since compounds other than ethanol (i.e., acetone) can also serve as P450IIE1 inducers, and since ethanol given with a normal fat-containing (35% of energy) diet is associated with acetonemia, hepatic steatosis and decreased body weight gain, the question has been raised whether induction is mediated specifically by ethanol or whether it might represent a nonspecific response to these other factors. This was investigated by varying both the mode of ethanol administration and the composition of the diet. By administering ethanol in the drinking water, or as part of a low-fat (5% of energy) liquid diet, a significant induction of P450IIE1 and of the activities of the microsomal ethanol oxidizing system and p-nitrophenol hydroxylase was demonstrated in the absence of any significant increase in blood acetone with minimal increase in liver total lipids. Induction of P450IIE1 was comparable with the low or normal fat-containing diets, but MEOS activity rose more with the latter, possibly reflecting a potentiating effect of dietary fat on ethanol oxidation by P-450 enzymes other than P450IIE1. When the lack of weight gain of the alcohol fed animals was mimicked in controls by decreasing the amount of diet ingested, no induction was observed. Varying the pattern of liquid diet feeding had no demonstrable differential effect. Thus, the induction of P450IIE1 after chronic ethanol consumption can be attributed to ethanol itself, but dietary fat can potentiate the induction of the microsomal ethanol oxidizing system and of p-nitrophenol hydroxylase.

Acetone↗
PubMed1988

Increased vitamin A in esophagus and lungs after moderate ethanol consumption.

Moderate ethanol consumption, at the level of 18% of total energy as part of a liquid diet, was found to result in a significant increase of total vitamin A content in the esophageal mucosa in rats fed normal-zinc-containing or zinc-supplemented diets. There was also an increase in total vitamin A content in the lungs after ethanol consumption, but the change was significant only in the zinc-supplemented group. In the liver, retinyl palmitate plus oleate decreased after ethanol, whereas free retinol, retinyl stearate, and linoleate increased. Ethanol consumption resulted in a modest decrease in hepatic zinc content when expressed per gram of liver, but not per total liver (per 100 gram of body weight). Although chronic ethanol consumption at the level of 18% of total energy did not affect total hepatic vitamin A, there was still a significant increase of vitamin A content in esophagus and lungs.

Alcoholism↗
PubMed1988

Venous, arterial, and arterialized-venous blood ammonia levels and their relationship to hepatic encephalopathy after propranolol.

To assess side effects of propranolol in the treatment of portal hypertension, we measured blood ammonia in 14 cirrhotics before and after administration of propranolol, and in six cirrhotics before and after placebo. We evaluated ammonia blood levels obtained from three sites: venous, arterial, and arterialized-venous, obtained by warming the forearm. Ammonia concentration of arterial and arterialized-venous blood were abnormal for all cirrhotics studied and significantly greater than the ammonia concentration of venous blood (p less than 0.01). When propranolol was administered to patients with alcoholic cirrhosis and marginal liver function, as reflected by ammonia levels above 60 microM, it caused a significant increase in ammonia levels in arterialized-venous and arterial, but not in venous, blood (p less than 0.05). Propranolol caused a significant increase in the time required to perform sensitive psychometric tests (p less than 0.05). Encephalopathy usually became clinically apparent when the mean of the arterial and arterialized-venous blood ammonia levels rose above 122 microM.

Ammonia↗
PubMed1987

Characterization of the cytochrome P-450 monooxygenase system of hamster liver microsomes. Effects of prior treatment with ethanol and other xenobiotics.

The cytochrome P-450 monooxygenase system of hamster liver microsomes and its response to prior treatment with ethanol and other xenobiotics have been examined. Male Syrian golden hamsters were administered ethanol (ETOH), phenobarbital (PB), 5,6-benzoflavone (BF) or isoniazid (INH). Each treatment resulted in a moderate increase (20-60%) in the specific content of liver microsomal cytochrome P-450 along with a unique hemeprotein ferrous carbonyl Soret maximum. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis of liver microsomes revealed distinctive changes in protein banding patterns in the cytochrome P-450 (45-60 kDa) region with each treatment. NADPH: cytochrome c reductase activity was increased by both PB and INH, whereas cytochrome b5 content was increased by INH only. Microsomal oxidation of ETOH and aniline p-hydroxylation (expressed per nmol cytochrome P-450) were enhanced dramatically by ETOH and INH, whereas PB and BF had no effect on these enzymatic activities. Both ETOH and INH also increased zoxazolamine 6-hydroxylation but, in contrast to other rodent species, this drug-metabolizing activity was decreased in hamster liver microsomes after treatment with either PB or BF. Microsomal benzphetamine N-demethylation was decreased by ETOH, INH and BF administration and was only modestly enhanced after treatment with PB. ETOH and INH had no effect on the O-deethylation of 7-ethoxycoumarin, and enzymatic activity increased by BF but decreased by PB. These results demonstrate that the cytochrome P-450-dependent monooxygenase system of hamster liver microsomes responds to treatment with ETOH and other xenobiotics in a manner that is quantitatively and, in certain respects, qualitatively different from that reported for the rat, rabbit, and mouse.

Animals↗
PubMed1987

Purification and characterization of human liver cytochrome P-450-ALC.

Cytochrome P-450-ALC, an ethanol-oxidizing form of microsomal cytochrome P-450 (P-450), has been purified from human liver. P-450-ALC (Mr = 54,000 daltons) is a low-spin ferric hemeprotein with a CO-reduced Soret maximum at 452 nm, and has an NH2-terminal amino acid sequence nearly identical to that deduced from a human P-450-ALC cDNA clone. In a reconstituted system, P-450-ALC oxidizes ethanol and aniline at turnover rates (12.2 and 7.3 nmol min-1, respectively) 10-fold greater than two other human P-450 isozymes (termed P-450-B and P-450-C) purified from the same liver. Both P-450-ALC and P-450-C effectively demethylate N-nitrosodimethylamine (NDMA) at low substrate concentrations (0.5 mM), especially in the presence of cytochrome b5. Our results provide direct evidence for a liver P-450 isozyme in humans with catalytic properties similar to the related alcohol-inducible rodent P-450s and also reveal a new human NDMA demethylase.

Amino Acid Sequence↗
PubMed1987

The contribution of the stomach to ethanol oxidation in the rat.

To estimate the amount of ethanol that can be oxidized in the stomach, steady-state conditions were created in a group of fed rats by giving a loading dose of ethanol (2 g/kg body wt I.V.) followed by continuous infusion either intravenously or intragastrically. The rate of ethanol oxidation was calculated from the rate of infusion required to maintain steady blood levels of approximately 30 mM for at least 3 hours. Gastrointestinal ethanol concentrations and total contents also remained steady. The rate of ethanol oxidation was 19.3% faster during intragastric than during intravenous infusion (p less than 0.01). When measured at the prevailing luminal ethanol concentration (145 mM) and expressed per body weight, the gastric ADH activity represented 14% of the hepatic activity at 30 mM ethanol, suggesting that gastric ADH activity could account for most of the increased rate of oxidation when ethanol is given intragastrically. Thus, gastric ethanol oxidation by a high Km ADH in the rat represents a significant fraction of the total rate of ethanol oxidation and it is therefore one of the factors which determines the bioavailability of orally administered ethanol.

Alcohol Dehydrogenase↗
PubMed1987

Ethanol-metabolizing pathways in deermice. Estimation of flux calculated from isotope effects.

The apparent deuterium isotope effects on Vmax/Km (D(V/K] of ethanol oxidation in two deermouse strains (one having and one lacking hepatic alcohol dehydrogenase (ADH] were used to calculate flux through the ADH, microsomal ethanol-oxidizing system (MEOS), and catalase pathways. In vitro, D(V/K) values were 3.22 for ADH, 1.13 for MEOS, and 1.83 for catalase under physiological conditions of pH, temperature, and ionic strength. In vivo, in deermice lacking ADH (ADH-), D(V/K) was 1.20 +/- 0.09 (mean +/- S.E.) at 7.0 +/- 0.5 mM blood ethanol and 1.08 +/- 0.10 at 57.8 +/- 10.2 mM blood ethanol, consistent with ethanol oxidation principally by MEOS. Pretreatment of ADH- animals with the catalase inhibitor 3-amino-1,2,4-triazole did not significantly change D(V/K). ADH+ deermice exhibited D(V/K) values of 1.87 +/- 0.06 (untreated), 1.71 +/- 0.13 (pretreated with 3-amino-1,2,4-triazole), and 1.24 +/- 0.13 (after the ADH inhibitor, 4-methylpyrazole) at 5-7 mM blood ethanol levels. At elevated blood ethanol concentrations (58.1 +/- 2.4 mM), a D(V/K) of 1.37 +/- 0.21 was measured in the ADH+ strain. For measured D(V/K) values to accurately reflect pathway contributions, initial reaction conditions are essential. These were shown to exist by the following criteria: negligible fractional conversion of substrate to product and no measurable back reaction in deermice having a reversible enzyme (ADH). Thus, calculations from D(V/K) indicate that, even when ADH is present, non-ADH pathways (mostly MEOS) participate significantly in ethanol metabolism at all concentrations tested and play a major role at high levels.

Acetates↗
PubMed1987

Respective roles of the microsomal ethanol oxidizing system and catalase in ethanol metabolism by deermice lacking alcohol dehydrogenase.

To evaluate the roles of MEOS (microsomal ethanol oxidizing system) and catalase in non-alcohol dehydrogenase (ADH) ethanol metabolism, MEOS and catalase activities in vitro and ethanol oxidation rates in hepatocytes from ADH-negative deermice were measured after treatment with catalase inhibitors and/or a stimulator of H2O2 generation. Inhibition of ethanol peroxidation by 3-amino-1,2,4-triazole (aminotriazole) was found to be greater than 85% up to 3 h and 80% at 6 h in liver homogenates. Urate (1 mM) which stimulates H2O2 production in living systems, increased ethanol oxidation fourfold in control but not in cells from aminotriazole-treated animals, documenting effective inhibition of catalase-mediated ethanol peroxidation by aminotriazole. While aminotriazole slightly depressed (15%) basal ethanol oxidation in hepatocytes, in vitro experiments showed a similar decrease in MEOS activity after aminotriazole pretreatment. Azide (0.1 mM), a potent inhibitor of catalase in vitro, also did not affect ethanol oxidation in control cells. By contrast, 1-butanol, a competitive inhibitor of MEOS, but neither a substrate nor an inhibitor of catalase, decreased ethanol oxidation rates in a dose-dependent manner. These results show that, in deermice lacking ADH, catalase plays little if any role in hepatic ethanol oxidation, and that MEOS mediates non-ADH metabolism.

1-Butanol↗
PubMed1987

Acetaldehyde binding increases the catabolism of rat serum low-density lipoproteins.

Acetaldehyde was found to form adducts with rat serum lipoproteins. The binding of [14C]acetaldehyde to lipoproteins was studied at low concentrations which are known to exist during ethanol oxidation. The amount of lipoprotein adducts was a linear function of acetaldehyde concentration up to 250 microM. Incubation of rat plasma low-density lipoproteins (LDL) with 200 microM acetaldehyde increased the disappearance rate of the 3H-label from the cholesterol ester moiety of LDL injected into normal rats. The data show that even low concentrations of acetaldehyde are capable of affecting LDL metabolism. These findings may provide an explanation for the low concentrations of serum LDL in alcoholics.

Acetaldehyde↗
PubMed1987

Red blood cells: a new major modality for acetaldehyde transport from liver to other tissues.

After alcohol ingestion, an amount of acetaldehyde much larger than previously appreciated by measurements in plasma is released from the splanchnic areas, travels reversibly bound to the red blood cells, and is taken up by extrahepatic tissues. The magnitude of this new modality for acetaldehyde transport is markedly enhanced in alcoholics and may contribute to acetaldehyde toxicity in extrahepatic tissues.

Acetaldehyde↗
PubMed1987

Purification of NADPH:cytochrome c (cytochrome P-450) reductase from hamster liver microsomes by detergent extraction and affinity chromatography.

NADPH:cytochrome c (cytochrome P-450) reductase (Fp) from hamster liver microsomes has been purified to near homogeneity using a simple and rapid method. Microsomes were treated with the detergent Chaps (3-[(3-cholamidopropyl)dimethylammonio]propanesulfonic acid) in combination with 0.07% protamine sulfate and then centrifuged to pellet insoluble material. While over 60% of the total microsomal protein was solubilized, all Fp activity remained in the pellet. Fp was extracted from the Chaps-insoluble material using a combination of the detergents sodium cholate and Lubrol PX. This treatment resulted in a fivefold increase in Fp specific activity and allowed direct processing of the enriched Fp fraction by 2',5'-ADP agarose affinity chromatography. The purified Fp had a total flavin content of 23 nmol/mg protein (flavin adenine dinucleotide:flavin mononucleotide ratio = 1:1), a specific activity of 26,000 units/mg protein at 22 degrees C using cytochrome c as electron acceptor, and migrated as a single band on sodium-dodecyl sulfate-polyacrylamide gel electrophoresis with a relative molecular weight of 76,000. The purity, specific activity, and yield were nearly identical to results obtained when the flavoprotein was purified by conventional methods. This procedure eliminates the need for anion-exchange chromatography and allows for the rapid purification of large amounts of Fp suitable for use in studies concerning cytochrome P-450-mediated drug metabolism. Importantly, this method is equally effective when used to purify Fp from rat liver microsomes.

Animals↗
PubMed1987

NAD+-dependent retinol dehydrogenase in liver microsomes.

A microsomal NAD+-dependent retinol dehydrogenase is being described with optimal activity at physiological pH. The enzyme was present in liver microsomes of rats and also in a strain of deermice which lacks the cytosolic retinol dehydrogenase. Unlike the latter enzyme, the microsomal retinol dehydrogenase was not inhibited by either ethanol or 4-methylpyrazole; its activity was insensitive to CO and not oxygen dependent, in contradistinction with that of the microsomal cytochrome P-450 and NADPH-dependent retinol oxidase. Chronic ethanol consumption resulted in an increased activity of the microsomal retinol dehydrogenase which may contribute to hepatic retinol depletion, especially in view of the insensitivity of the enzyme to ethanol inhibition.

Alcohol Oxidoreductases↗
PubMed1987

Effect of ethanol and vitamin A deficiency on epithelial cell proliferation and structure in the rat esophagus.

An increased risk of cancer of the esophagus has been reported in alcoholics and in populations with low dietary vitamin A consumption. As cancer is a disorder of cell proliferation and differentiation, we have assessed the combined effects of ethanol and vitamin A deficiency on cell proliferation and structure of the esophagus. Weanling male rats were fed liquid diets with either a standard amount of vitamin A or lacking vitamin A for 8 wk. Littermates were pair-fed the same diets with carbohydrate (36% of calories) replaced by ethanol. Rats were given [3H]thymidine 1 h before death, and the labeling index of the proliferative basal cells was determined on radioautographs. In rats fed the normal vitamin A diet with or without ethanol, plasma vitamin A was normal. Hepatic vitamin A was markedly decreased, whereas esophageal vitamin A was increased after ethanol feeding. Ethanol feeding resulted in a twofold increase in basal cell labeling index (14.6 +/- 0.7 vs. 6.8 +/- 0.8; p less than 0.001). The thickness of the epithelium and the morphology of basal cells were not altered by ethanol feeding. In rats fed the vitamin A-deficient diet with or without ethanol, plasma vitamin A was extremely low, and hepatic and esophageal vitamin A were unmeasurable. The epithelium was thin (with a 50% reduction in thickness) and showed abnormalities of basal cells and increased production of keratohyalin granules, changes suggesting a disorder in the epithelial differentiation. This altered differentiation caused by vitamin A deficiency was not affected by ethanol consumption. Ethanol feeding again resulted in an increase in the basal cell labeling index (13.2 +/- 1.6 vs. 4.8 +/- 0.7; p less than 0.001). Vitamin A deficiency had no effect on basal cell proliferation. Therefore, the stimulatory effect of ethanol on cell proliferation is independent of vitamin A deficiency. Nevertheless, the combined actions of ethanol and vitamin A deficiency may have a synergistic effect on the susceptibility of the esophagus to carcinogens.

Animals↗
PubMed1987

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC Working Paper No. 15/2. Metabolism and metabolic effects of ethanol, including interaction with drugs, carcinogens and nutrition.

Different pathways of alcohol metabolism, the alcohol dehydrogenase pathway, the microsomal ethanol-oxidizing system and the catalase pathway are discussed. Alcohol consumption leads to accelerated ethanol metabolism by different mechanisms including an increased microsomal function. Microsomal induction leads to interactions of ethanol with drugs, hepatotoxic agents, steroids, vitamins and to an increased activation of mutagens/carcinogens. A number of ethanol-related complications may be explained by the production of its first metabolite, acetaldehyde, such as alterations of mitochondria, increased lipid peroxidation and microtubular alterations with its adverse effects on various cellular activities, including disturbances of cell division. Nutritional factors in alcoholics such as malnutrition are discussed especially with respect to its possible relation to cancer.

Biotransformation↗