[Clinical biochemistry of alcohol and its metabolic and hepatic effects].
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Acetaldehyde↗
Biomedical subjects
C S Lieber
Publications and source records attributed to C S Lieber.
Method of acetaldehyde measurement with minimal artifactual formation in red blood cells and plasma of actively drinking subjects with alcoholism.
After alcohol consumption, a substantial amount of acetaldehyde that is reversibly bound to protein and nonprotein components of the red blood cells circulates in the blood and could cause extrahepatic toxicity. However, acetaldehyde measurement in human red blood cells is hampered by considerable ex vivo artifactual formation as a result of nonenzymatic oxidation of ethanol during protein precipitation. To eliminate this source of artifactual formation, free and reversibly bound acetaldehyde were trapped with semicarbazide from red blood cell hemolysates, and both the stroma and the hemoglobin were sequentially removed by centrifugation and ion-exchange chromatography in carboxymethyl Sephadex, respectively. The eluted semi-carbazone was dissociated with perchloric acid, and the acetaldehyde that was released in the protein-free supernatants was measured by head-space gas chromatography. Maximal retention of hemoglobin by carboxymethyl Sephadex and complete recovery of acetaldehyde and ethanol were achieved at a pH of 5.3. The artifactual formation decreased from 2.62 +/- 0.32 mumol of acetaldehyde per millimole of ethanol in the initial hemolysates to 1.38 +/- 0.20 mumol after removal of the stroma and to a level that is comparable to measurements in plasma (0.09 +/- 0.02 mumol) after removal of both the stroma and the hemoglobin. In 12 actively drinking subjects with alcoholism, with blood ethanol levels that ranged between 9 and 81 mmol/L, the concentrations of acetaldehyde in red blood cells (11.50 +/- 1.46 mumol/L; range: 7.5 to 22 mumol/L) were minimally affected by blood ethanol levels and were three times as high as those in the plasma (3.74 +/- 1.49 mumol/L).(ABSTRACT TRUNCATED AT 250 WORDS)
Acetaldehyde↗
Effects of ethanol consumption on bioactivation and hepatotoxicity of N-nitrosodimethylamine in rats.
To study the effects of ethanol on the hepatotoxicity of N-nitrosodimethylamine (NDMA), 5 mg NDMA/kg body weight was injected intraperitoneally 3 times a week for 6 weeks into rats pair-fed liquid diets containing 36% of energy either as ethanol or as additional carbohydrates. Another group of rats was pair-fed with the same diets but injected with saline instead of NDMA. Co-administration of ethanol and NDMA produced much higher elevations of serum alanine and aspartate aminotransferase and glutamic dehydrogenase activities than the administration of either agent alone. The combined treatment also slightly increased focal necrosis, whereas other liver lesions (steatosis and fibrosis) and the functional impairment of mitochondrial respiration were not affected significantly. Microsomal low Km NDMA demethylation, as well as NDMA denitrosation, were inhibited markedly by incubation with an antibody against P450IIE1, suggesting the involvement of this alcohol-inducible P450 in both NDMA bioactivation reactions. The addition of ethanol inhibited P450-dependent demethylation and denitrosation of NDMA in liver microsomes, whereas both activities were enhanced markedly by chronic ethanol administration. At ethanol concentrations similar to those prevailing in the blood of alcohol-fed animals at the time of NDMA administration, hepatic microsomal demethylation and denitrosation remained significantly higher in ethanol-fed rats given NDMA than in controls. Our results suggest that bioactivation plays a critical role in the hepatotoxicity of NDMA and its aggravation by chronic alcohol consumption.
Alanine Transaminase↗
Chronic alcoholic gastritis. Roles of alcohol and Helicobacter pylori.
We assessed the relative roles of alcohol and infection with Helicobacter pylori in the pathogenesis of chronic gastritis in alcoholic patients. Helicobacter pylori was found in 14 of 18 alcoholics with dyspepsia and was associated with chronic antral gastritis. Gastric biopsy specimens were normal in four H pylori-negative alcoholics. Studies were repeated 3 to 4 weeks after controlled abstinence. There was no change in histologic findings during this period, indicating that alcohol itself was not the major causative agent. We then eliminated H pylori in 10 subjects by giving triple therapy (bismuth subsalicylate, amoxicillin, and metronidazole). Treatment for H pylori was associated with almost complete normalization of histologic findings. Four control subjects who received antacids alone showed no improvement. Dyspeptic symptoms in H pylori-positive patients significantly improved after elimination of this organism, whereas there was no change with antacid treatment.
Adult↗
Effects of H2-receptor antagonists on gastric alcohol dehydrogenase activity.
Inhibition of gastric alcohol dehydrogenase (ADH) activity by cimetidine results in elevated blood levels of ethanol after moderate consumption. To search for alternative H2-blockers lacking such an effect, we compared cimetidine, ranitidine, nizatidine, and famotidine. They inhibited rat gastric ADH noncompetitively, with a Ki for ethanol oxidation of 0.68 mM for cimetidine, 0.5 mM for ranitidine, 1 mM for nizatidine, and 4.5 mM for famotidine. These concentrations are higher than therapeutic plasma levels, but intracellular concentrations in the gastric mucosa (assessed with [3H]cimetidine and [14C]famotidine) were at least 10- and 2-fold greater than in the blood, respectively. These results suggests that, given at therapeutic doses in vivo, the degree of inhibition by cimetidine and ranitidine should be significant and comparable, that by nizatidine should be smaller, and that by famotidine should be negligible. These drugs also exerted either mixed or competitive inhibition of rat hepatic ADH, but the effects of cimetidine and famotidine were observed at concentrations unlikely to occur in vivo. Thus, in alcoholics and in social drinkers who require treatment with H2-receptor antagonists, famotidine might be preferable to the other H2 blockers tested.
Alcohol Dehydrogenase↗
Severity of Helicobacter-induced gastric injury correlates with gastric juice ammonia.
We postulated that ammonia produced by Helicobacter pylori may contribute to gastric mucosal injury. This hypothesis was evaluated in Helicobacter-positive patients with chronic renal failure in whom a high urea concentration might amplify this phenomenon. Gastric urea and ammonia were measured, and the severity of gastritis was evaluated by counting mononuclear and polymorphonuclear cells. High gastric ammonia and low urea in Helicobacter-positive patients, and the converse in Helicobacter-negative subjects, were observed. There was a significant correlation between gastric ammonia and interstitial polymorphonuclear leukocytes infiltration (P less than 0.05), suggesting a causal link. Eradication of Helicobacter pylori was associated with a decrease of ammonia and an increase of urea (P less than 0.01). The significant correlation between the severity of gastric inflammation and the gastric juice ammonia concentration suggests that ammonia may play a pathogenic role in Helicobacter-associated gastric injury.
Ammonia↗
The effect of the prostaglandin analogue-misoprostol on rat liver mitochondria after chronic alcohol feeding.
Rats fed ethanol (36% of total calories in a nutritionally adequate liquid diet) for 5 weeks develop functional alterations of hepatic mitochondria and steatosis of the liver. At the fatty liver stage, ADP-stimulated respiration of mitochondria was depressed in ethanol fed rats by 30% (p less than 0.001) with glutamate + malate and by 23% (p less than 0.001) with succinate as substrates. A similar decrease was noted in the respiratory control ratio (RCR) (34% and 29%, respectively). The total lipid content of the liver increased 2.6 fold (p less than 0.001). Mitochondrial dysfunction could be prevented, in part, by the treatment with a synthetic derivative of prostaglandin E1, misoprostol, at a mean daily dose of 80 micrograms/kg of body weight. The RCR with glutamate + malate as substrates was improved by 36% (p less than 0.05). We conclude that misoprostol attenuates several functional alterations in liver mitochondria during alcohol feeding.
Alprostadil↗
Lack of alcohol dehydrogenase isoenzyme activities in the stomach of Japanese subjects.
Alcohol dehydrogenase (ADH) isoenzymes different from those of the liver were shown to be present in the human gastric mucosa. Two ADH activity bands present in the gastric mucosa of surgical specimens from all 7 black and 11 white Americans studied were absent in 14 and barely detectable in 3 of 21 Japanese subjects evaluated. Similar ethnic differences pertained to both genders and were independent of the gastric pathology. The mobility of these bands on starch gel electrophoresis corresponded to those recently reported and named mu-ADH or sigma-ADH. The absence of these bands was associated with a 70% decreased capacity to reduce m-nitrobenzaldehyde, a preferred substrate for sigma-ADH, suggesting that the bands missing from the Japanese stomachs comprise this isoenzyme.
Alcohol Dehydrogenase↗
Effects of ethanol and hepatic vitamin A on the proliferation of lipocytes in regenerating rat liver.
The effects of ethanol and hepatic vitamin A on lipocyte proliferation were studied in regenerating rat livers. Positive identification of proliferating lipocytes was achieved by a double immunostaining sequence for cytoplasmic desmin and bromodeoxyuridine-labelled nuclei. Ethanol administration caused a 76 and 36% reduction in labelling indices of lipocytes 2 and 3 days after hepatectomy, respectively, thereby delaying the onset of the proliferative peak of lipocytes by 1 day compared to the control. Hepatic vitamin A did not decrease until 4 days after hepatectomy. The relationship between hepatic vitamin A and lipocyte proliferation was further evaluated in rats fed diets containing four different amounts of vitamin A. Despite the striking differences in liver vitamin A levels, the proliferative activity of lipocytes was unaffected, as measured at the peak of lipocyte proliferation 2 days after hepatectomy. These data indicate that ethanol ingestion suppresses the proliferative response of lipocytes to partial hepatectomy but that this ethanol effect is independent of changes of vitamin A levels in the liver.
Adipose Tissue↗
Alcohol, liver, and nutrition.
Until two decades ago, dietary deficiencies were considered to be the major reason why alcoholics developed liver disease. As the overall nutrition of the population improved, more emphasis was placed on secondary malnutrition. Direct hepatotoxic effects of ethanol were also established, some of which were linked to redox changes produced by reduced nicotinamide adenine dinucleotide (NADH) generated via the alcohol dehydrogenase (ADH) pathway. It was also determined that ethanol can be oxidized by a microsomal ethanol oxidizing system (MEOS) involving cytochrome P-450: the newly discovered ethanol-inducible cytochrome P-450 (P-450IIE1) contributes to ethanol metabolism, tolerance, energy wastage (with associated weight loss), and the selective hepatic perivenular toxicity of various xenobiotics. P-450 induction also explains depletion (and enhanced toxicity) of nutritional factors such as vitamin A. Even at the early fatty-liver stage, alcoholics commonly have a very low hepatic concentration of vitamin A. Ethanol administration in animals was found to depress hepatic levels of vitamin A, even when administered with diets containing large amounts of the vitamin, reflecting, in part, accelerated microsomal degradation through newly discovered microsomal pathways of retinol metabolism, inducible by either ethanol or drug administration. The hepatic depletion of vitamin A was strikingly exacerbated when ethanol and other drugs were given together, mimicking a common clinical occurrence. Hepatic retinoid depletion was found to be associated with lysosomal lesions and decreased detoxification of chemical carcinogens. To alleviate these adverse effects, as well as to correct problems of night blindness and sexual inadequacies, the alcoholic patient should be provided with vitamin A supplementation. Such therapy, however, is complicated by the fact that in excessive amounts vitamin A is hepatotoxic, an effect exacerbated by long-term ethanol consumption. This results in striking morphologic and functional alterations of the mitochondria with leakage of mitochondrial enzymes, hepatic necrosis, and fibrosis. Thus, treatment with vitamin A and other nutritional factors (such as proteins) is beneficial but must take into account a narrowed therapeutic window in alcoholics who have increased needs for such nutrients, but also display an enhanced susceptibility to their adverse effects. Massive doses of choline also exerted some toxic effects and failed to prevent the development of alcoholic cirrhosis. Acetaldehyde (the metabolite produced from ethanol by either ADH or MEOS) impairs hepatic oxygen utilization and forms protein adducts, resulting in antibody production, enzyme inactivation, and decreased DNA repair. It also enhances pyridoxine and perhaps folate degradation and stimulates collagen production by the vitamin A storing cells (lipocytes) and myofibroblasts.(ABSTRACT TRUNCATED AT 400 WORDS)
Acetaldehyde↗
Metabolism of ethanol and associated hepatotoxicity.
Over the last three decades, direct hepatotoxic effects of ethanol were established, some of which were linked to redox changes produced by NADH generated via the alcohol dehydrogenase (ADH) pathway and shown to affect the metabolism of lipids, carbohydrates, proteins, and purines. It was also determined that ethanol can be oxidized by a microsomal ethanol oxidizing system (MEOS) involving a specific cytochrome P-450; this newly discovered ethanol-inducible cytochrome P-450 (P-450 IIEi) contributes to ethanol metabolism, tolerance, energy wastage (with associated weight loss), and the selective hepatic perivenular toxicity of various xenobiotics. Their activation by P-450IIEi now provides an understanding of the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, over-the-counter analgesics, and chemical carcinogens. P-450 induction also explains depletion (and toxicity) of nutritional factors such as vitamin A. As a consequence, treatment with vitamin A and other nutritional factors is beneficial, but must take into account a narrowed therapeutic window in alcoholics who have increased needs for nutrients and also display an enhanced susceptibility to some of their adverse effects. Acetaldehyde (the metabolite produced from ethanol by either ADH or MEOS) impairs hepatic oxygen utilization and forms protein adducts, resulting in antibody production, enzyme inactivation, and decreased DNA repair. It also stimulates collagen production by the vitamin A storing cells (lipocytes) and myofibroblasts, and causes glutathione depletion. Supplementation with S-adenosyl-L-methionine partly corrects the depletion and associated mitochondrial injury, whereas administration of polyunsaturated lecithin opposes the fibrosis. Thus, at the cellular level, the classic dichotomy between the nutritional and toxic effects of ethanol has now been bridged. The understanding of how the ensuing injury eventually results in irreversible scarring or cirrhosis may provide us with improved modalities for treatment and prevention.
Journal Article↗
Perspectives: do alcohol calories count?
Chronic consumption of substantial amounts of alcohol is not associated with the expected effect on body weight. Isocaloric substitution of carbohydrates by ethanol results in weight loss, and addition of ethanol to an otherwise normal diet does not produce the expected weight gain. This energy deficit cannot be explained by maldigestion or malabsorption but has been attributed to induction of the microsomal ethanol oxidizing system (a metabolic pathway that oxidizes ethanol without associated chemical energy production), increased sympathetic tone and associated thermogenesis, and/or enhanced ATP breakdown (with increased purine catabolism) secondary to the acetate produced from ethanol. All these hypotheses do not fully explain the lack of weight deficit when alcohol is consumed with a very-low-fat diet, which suggests that an alteration in the energy utilization derived from fat plays a major role, possibly through uncoupling of oxidation with phosphorylation in mitochondria damaged by chronic ethanol consumption.
Adult↗
Ethanol consumption inhibits fetal DNA methylation in mice: implications for the fetal alcohol syndrome.
Acute ethanol administration (3 g/kg twice a day) to pregnant mice, from the 9th thru the 11th day of gestation, resulted in hypomethylation of fetal deoxyribonucleic acid (DNA). Nuclei isolated from the fetuses of the ethanol-treated mice had lower levels of methylase activity relative to controls even in the presence of excess S-adenosylmethionine, which serves as the methyl donor for the enzyme DNA methyltransferase. Acetaldehyde, at concentrations as low as 3 to 10 microM, inhibited DNA methyltransferase activity in vitro. Since DNA methylation is thought to play an important role in the regulation of gene expression during embryogenesis, ethanol-associated alterations in fetal DNA methylation may contribute to the developmental abnormalities seen in the fetal alcohol syndrome.
5-Methylcytosine↗
Hepatic, metabolic and toxic effects of ethanol: 1991 update.
Until two decades ago, dietary deficiencies were considered to be the only reason for alcoholics to develop liver disease. As the overall nutrition of the population improved, more emphasis was placed on secondary malnutrition and direct hepatotoxic effects of ethanol were established. Ethanol is hepatotoxic through redox changes produced by the NADH generated in its oxidation via the alcohol dehydrogenase pathway, which in turn affects the metabolism of lipids, carbohydrates, proteins, and purines. Ethanol is also oxidized in liver microsomes by an ethanol-inducible cytochrome P-450 (P-450IIE1) that contributes to ethanol metabolism and tolerance, and activates xenobiotics to toxic radicals thereby explaining increased vulnerability of the heavy drinker to industrial solvents, anesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens, and even nutritional factors such as vitamin A. In addition, ethanol depresses hepatic levels of vitamin A, even when administered with diets containing large amounts of the vitamin, reflecting, in part, accelerated microsomal degradation through newly discovered microsomal pathways of retinol metabolism, inducible by either ethanol or drug administration. The hepatic depletion of vitamin A is strikingly exacerbated when ethanol and other drugs were given together, mimicking a common clinical occurrence. Microsomal induction also results in increased production of acetaldehyde. Acetaldehyde, in turn, causes injury through the formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, and alterations in microtubules, plasma membranes and mitochondria with a striking impairment of oxygen utilization. Acetaldehyde also causes glutathione depletion and lipid peroxidation, and stimulates hepatic collagen production by the vitamin A storing cells (lipocytes) and myofibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetaldehyde↗
Effect of concentration of ingested ethanol on blood alcohol levels.
The effect of the concentration of ingested ethanol on the resulting blood alcohol concentrations (BAC) was tested in both humans and rats. In humans, when 0.3 g/kg body weight ethanol was ingested postprandially, the mean area under the blood alcohol curve (AUC) and the mean peak BAC were significantly lower with a concentrated (40% w/v) than with a dilute (4%) solution. Similarly, rats in the fed state exhibited decreasing mean AUCs with increasing concentrations (4%, 16%, and 40%) of intragastrically administered ethanol (1.0 g/kg). Pharmacokinetic analysis comparing intragastric and intraperitoneal administration of ethanol to rats indicated that the more concentrated solution resulted in less alcohol reaching the systemic circulation (4%: 0.896 +/- 0.074 g/kg: 16% 0.772 +/- 0.072 g/kg; 40%: 0.453 +/- 0.037 g/kg) and suggested that this affect could be attributed to two factors: increased gastric retention of ethanol (4%: 0.109 +/- 0.024 g/kg; 16%: 0.102 +/- 0.016 g/kg; 40%: 0.214 +/- 0.042 g/kg) and a large increase in first-pass metabolism (4%; 0.004 +/- 0.054 g/kg; 16%: 0.145 +/- 0.048 g/kg; 40%: 0.329 +/- 0.044 g/kg). In contrast to the results in the fed state, in humans fasted overnight the concentration of alcohol consumed (4%, 16%, and 40%) had no significant effect on mean AUCs. In fasted rats, mean AUCs after intragastric intubation of the two lower concentrations of ethanol (4% and 16%) were comparable to those found after intraperitoneal injection, and only the highest ethanol concentration (40%) produced a lower mean AUC.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Isoelectric focusing/western blotting: a novel and practical method for quantitation of carbohydrate-deficient transferrin in alcoholics.
Carbohydrate-deficient transferrin (CDT) has been described as the single, most accurate marker of chronic alcohol consumption. Rapid, sensitive, and specific measurement of serum CDT levels can thus provide important clinical information concerning patient diagnosis and treatment. To date, however, methods used for assessing CDT concentrations [e.g., analytical isoelectric focusing combined with immunofixation and micro anion-exchange chromatography followed by radioimmunoassay (RIA)] have not been practical enough for widespread laboratory application. In the present study, we examined the use of a different technique, namely isoelectric focusing (IEF) combined with Western blotting (IEF/WB). Serum proteins (20-40 micrograms) were first focused according to isoelectric points (pI) on high-resolution agarose IEF gels (ampholyte pH range of 5-8) containing nonionic detergent. The focused proteins were transferred electrophoretically to nitrocellulose filters, and then stained immunochemically with antihuman transferrin IgG. IEF/WB completely resolved CDT (focusing at pI 5.7 and 5.9) from other serum transferring isoforms, as assessed with neuraminidase-generated CDT standards. Computerized densitometric scanning of the immunoblots allowed CDT levels to be quantitated directly rather than as a quotient. Serum CDT content determined by IEF/WB was highly correlated (r2 = 0.962; n = 17) with values determined previously by RIA. In a larger subject group, CDT levels (mg/liter) measured by IEF/WB were 139 +/- 54 in recently-drinking alcoholics (n = 58), 81 +/- 8 in abstaining alcoholics (n = 7), and 68 +/- 16 in healthy control subjects (n = 16).(ABSTRACT TRUNCATED AT 250 WORDS)
Alcoholism↗
Gender differences in the response of hepatic fatty acids and cytosolic fatty acid-binding capacity to alcohol consumption in rats.
To investigate possible gender differences in the response of hepatic fatty acids and cytosolic fatty acid-binding capacity to ethanol consumption, both female and male rats (41 days of age) were pair fed liquid diets (with a littermate of the same sex) for 28 days. The diets contained 36% of energy either as ethanol or as additional carbohydrate. After ethanol feeding, the hepatic concentration of fatty acids increased 155% in females (P less than 0.01), whereas there was only a trend for an increase (22%) in males. This was associated with a much smaller increase of cytosolic fatty acid-binding capacity in females (58%) than in males (161%). Whereas the ethanol-induced increase in fatty acid-binding capacity provided an ample excess of binding sites for the fatty acids in males, the increase in females was barely sufficient for the binding of the large increase of fatty acids produced by ethanol in the females. The cytosolic protein responsible for this binding, the liver fatty acid-binding protein of the cytosol (L-FABPc), also promotes esterification of the fatty acids. In keeping with the postulated role of this protein, the ethanol-induced increases in hepatic triacylglycerols, phospholipids, and cholesterol esters were smaller in females than in males. The gender difference in cholesterol esters was associated with parallel changes in acyl-CoA transferase activity. A possible implication of the relatively small and most likely inadequate increase in liver fatty acid-binding capacity and fatty acid esterification during alcohol consumption in the females is that under these circumstances the risk for development of a potentially deleterious accumulation of fatty acids in the liver is increased, thereby contributing to the enhanced vulnerability of females to alcohol-induced hepatotoxicity.
Alcohol Drinking↗