Abstract: Evidence for the existence of increased lipid peroxidation in the liver after ethanol administration to rats is discussed. A criticism of the methods used to measure lipid peroxidation is also given. Most authors who are in favour of the presence of lipid peroxidation after ethanol have used the detection of thiobarbituric acid (TBA)-reacting substances as a measure of lipid peroxidation. This test is not entirely satisfactory, because: (1) it is not specific; (2) it mostly measures malonaldehyde, a substance of low toxicity, following a 1-2 hr incubation time; (3) several aldehydes produced during lipid peroxidation do not react with TBA. However, it is now clear that the aldehydes produced during lipid peroxidation are actively metabolized by homogenates, so differences in catabolism may influence the result of a TBA test. Measurement of the diene conjugation band, the other test usually used to detect lipid peroxidation, produces information only on the presence of dienes at a given moment, but does not give any information on the production or decomposition rates of such dienes. Thus differences in production or decomposition kinetics may mask the results. Notwithstanding these criticisms, most of the evidence at present is in favour of some involvement of lipid peroxidation in ethanol intoxication. One hypothesis is that of the direct impact of ethanol-derived free radicals. Another is that ethanol provokes the formation of oxygen free radical species, which can start lipid peroxidation either directly, or by exhausting anti-oxidant substances in the cell so as to change the balance in favour of increased peroxidation. Finally, a third hypothesis is that acetaldehyde, the main product of ethanol oxidation, is able to stimulate lipid peroxidation, possibly through the formation of free radicals, or depletion of levels of antioxidant substances. Experiments consisting of measuring total glutathione (GSH and GSSG) during lipid peroxidation stimulated by ethanol or acetaldehyde show, however, that GSH is totally converted into GSSG during the incubation, thus suggesting that the antioxidant trapped by acetaldehyde is not GSH. In isolated hepatocytes, disulfiram, an inhibitor of aldehyde dehydrogenase, does not prevent the GSH decrease caused by acetaldehyde, but can block the induced lipid peroxidation. The relevance of increased lipid peroxidation to the mechanism of the liver damage induced by ethanol remains unclear.

Abstract: When cultured on a defined diet, ethanol was an efficient substrate for lipid synthesis in wild-type Drosophila melanogaster larvae. At certain dietary levels both ethanol and sucrose could displace the other as a lipid substrate. In wild-type larvae more than 90% of the flux from ethanol to lipid was metabolized via the alcohol dehydrogenase (ADH) system. The ADH and aldehyde dehydrogenase activities of ADH were modulated in tandem by dietary ethanol, suggesting that ADH provided substrate for lipogenesis by degrading ethanol to acetaldehyde and then to acetic acid. The tissue activity of catalase was suppressed by dietary ethanol, implying that catalase was not a major factor in ethanol metabolism in larvae. The activities of lipogenic enzymes, sn-glycerol-3-phosphate dehydrogenase, fatty acid synthetase (FAS), and ADH, together with the triacylglycerol (TG) content of wild-type larvae increased in proportion to the dietary ethanol concentration to 4.5% (v/v). Dietary ethanol inhibited FAS and repressed the accumulation of TG in ADH-deficient larvae, suggesting that the levels of these factors may be subject to a complex feedback control.

Abstract: The metabolic effects of ethanol are due to a direct action of ethanol or its metabolites, changes in the redox state occurring during its metabolism, and modifications of the effects of ethanol by nutritional factors. Ethanol causes hyperglycemia or hypoglycemia depending on whether glycogen stores are adequate, inhibits protein synthesis, and results in fatty liver and in elevations in serum triglyceride levels. Increases in high-density lipoprotein cholesterol after ethanol ingestion may explain the lower risk of myocardial infarction and death from coronary disease after moderate drinking. Increases in serum lactate, resulting from the increased NADH/NAD+ ratio, and hyperuricemia, most likely the result of increased turnover of adenine nucleotides, are common transient effects of ethanol ingestion. Causes of vitamin deficiencies in alcoholism are decreased dietary intake, decreased intestinal absorption, and alterations in vitamin metabolism. Ethanol decreases thiamine absorption and decreases the enterohepatic circulation of folate. Acetaldehyde increases the degradation of pyridoxal 5'-phosphate by displacing it from its binding protein and making it susceptible to hydrolysis by membrane-bound alkaline phosphatase. Ethanol decreases hepatic vitamin A concentration and its conversion to active retinal, and modifies renal metabolism of vitamin D.

Abstract: The effects of several aldehydes and peroxides on growth and differentiation of normal human bronchial epithelial cells were studied. Cells were exposed to formaldehyde, acetaldehyde, benzoyl peroxide (BPO), or hydrogen peroxide (HPO). The effect of each agent on the following parameters was measured: ( a ) clonal growth rate; ( b ) squamous differentiation; ( c ) DNA damage; ( d ) ornithine decarboxylase activity; ( e ) nucleic acid synthesis; ( f ) aryl hydrocarbon hydroxylase activity; and ( g ) arachidonic acid and choline release. None of the agents were mitogenic, and their effects were assessed at concentrations which reduced growth rate (population doublings per day) to 50% of control. The 50% of control concentrations for the 6-h exposure were found to be 0.065 mm BPO, 0.21 mm formaldehyde, 1.2 mm HPO, and 30 mm acetaldehyde. BPO-exposed cells were smaller than controls (median cell planar area, 620 sq µm versus 1150 sq µm), and acetaldehyde-exposed cells were larger than controls (median cell planar area, 3200 sq µm). All agents increased the formation of cross-linked envelopes and depressed RNA synthesis more than DNA synthesis. HPO caused DNA single-strand breaks, while formaldehyde and BPO caused detectable amounts of both single-strand breaks and DNA-protein cross-links. Other effects included increased arachidonic acid and choline release due to HPO. The similarities and differences of the effects of these aldehydes and peroxides to those caused by tumor promoters are discussed.

Abstract: 1 Epidemiology of Alcohol Use and Its Gastrointestinal Complications.- 2 Ethanol Metabolism and Pathophysiology of Alcoholic Liver Diseases.- 3 Gamma-Glutamyltransferase and Other Markers for Alcoholism.- 4 Ethanol and Lipid Metabolism.- 5 Alcohol Effects on Albumin Synthesis.- 6 Metabolism and Toxicity of Acetaldehyde.- 7 Ethanol and Fibrogenesis in the Liver.- 8 Ethanol, Mallory Bodies, and the Microtubular System.- 9 Interaction of Ethanol with Drugs and Xenobiotics.- 10 Cytochrome P-450: Its Involvement in the Microsomal Ethanol Oxidation and Quantitative and Qualitative Changes After Chronic Alcohol Consumption.- 11 Ethanol and Carcinogenesis.- 12 Ethanol and Biological Membranes: Experimental Studies and Theoretical Considerations.- 13 Alcohol and Porphyrin Metabolism.- 14 Ethanol and Hepatic Cell Regeneration.- 15 Ethanol and the Immune System.- 16 Pathology of Alcoholic Liver Disease with Special Emphasis on Alcoholic Hepatitis.- 17 Clinical and Therapeutic Aspects of Alcoholic Liver Disease.- 18 Ethanol and the Endocrine System.- 19 Effect of Ethanol on Intestinal Morphology, Metabolism, and Function.- 20 Esophageal and Gastric Lesions in the Alcoholic.- 21 Acute and Chronic Actions of Alcohol on Pancreatic Exocrine Secretion in Humans and Animals.- 22 Subject Index.

Abstract: Disulfiram-like responses to various drug therapies are caused by elevated ethnol-derived blood acetaldehyde concentrations resulting from drug-induced inhibition of aldehyde dehydrogenase enzymes. We have found that the nitrate ester antianginal drugs, isosorbide dinitrate and nitroglycerin, are potent inhibitors of human erythrocyte aldehyde dehydrogenase. To further characterize this drug-induced enzyme inhibition, erythrocyte aldehyde dehydrogenase activities were measured in patients undergoing therapy with nitrate ester antianginals (isosorbide dinitrate and nitroglycerin) and sulfonylurea hypoglycemics (chlorpropamide and tolazamide). The erythrocyte enzyme was decreased by approximately 25% in sulfonylurea-treated patients, whereas in the nitrate ester-treated patients, an 88% inhibition was observed. The minimal enzyme inhibition in the sulfonylurea-treated group was unexpected because these therapies have well-documented disulfiram-like side effects. This weak inhibition contrasted with the severe inhibition observed in the nitrate ester-treated group where the disulfiram-like side effects are not considered a serious clinical problem. This apparent anomaly was attributed to differences in inhibition of the erythrocyte and liver aldehyde dehydrogenase by the parent drugs and their hepatic metabolites.

Abstract: Human leucocytes were incubated in the presence of vinyl acetate or acetaldehyde (10–20 mM) for 4 h at 37°C in vitro. DNA damage was analysed by alkaline elution. None of the compounds induced a detectable increase in the frequency of DNA strand breaks. Cells exposed to 5 Gy of X-ray immediately after treatment and before alkaline elution showed a clear, dose-dependent retardation of the elution rate in comparison with X-irradiated control cells. These results demonstrate that both vinyl acetate and acetaldehyde induce DNA cross-links in human cells.

Abstract: The hydrolysis of vinyl acetate (formation of acetic acid) has been studied in vitro with rat liver and lung microsomes, rat and human plasma and purified esterases (such as acetylcholine esterase, butyrylcholine esterase, carboxyl esterase). Characterization of the kinetic parameters revealed that rat liver microsomes and purified carboxyl esterase (from porcine liver) displayed the highest activity. In order to establish the rate of metabolism of vinyl acetate in vivo, rats were exposed in closed desiccator jar chambers, and gas uptake kinetics were studied. The decay of vinyl acetate was dose-dependent, indicating possible saturation of metabolic pathway(s). The maximal clearance (at lower concentrations) of vinyl acetate from the system (30 000 ml/h per kg body weight) was similar to the maximal ventilation rate in this species. This indicated that under conditions when metabolic enzymes are not saturated the metabolic rate is mainly determined by pulmonary uptake. The exposure of rats to vinyl acetate resulted in a transient exhalation of significant amounts of acetaldehyde into the closed exposure system. This indicates the presence of this metabolic intermediate of vinyl acetate in the organism in vivo.

Abstract: Glutathione and its metabolites were examined for reactivity to acetaldehyde. When acetaldehyde was incubated with glutathione alone, there was only a slight decrease of acetaldehyde, while an apparently equimolar reaction between acetaldehyde and free sulfhydryl was observed with the addition of γ-glutamyltranspeptidase. Cysteinylglycine, the first metabolite in the glutathione breakdown by γ-glutamyltranspeptidase, showed a rapid and equimolar reactivity to acetaldehyde and such was comparable to the reaction seen withl-cysteine ord-penicillamine. In light of the chemical structure, cysteinylglycine probably conjugates with acetaldehyde to form thiazolidinecarboxylic acid derivatives, 2-methyl-thiazolidine-4-carbonyl-glycine, and if so, the alteration of glutathione metabolism by acetaldehyde during ethanol intoxication warrants further attention.

Abstract: Acetaldehyde is the first oxidation product of ethanol, and under normal conditions it is oxidized further so rapidly that significant acetaldehyde concentrations can only be found in the liver. Aldehyde oxidase, xanthine oxidases, and aldehyde dehydrogenases are all capable of catalyzing aldehyde oxidation. The first two enzymes, however, have a broad substrate specificity and a low affinity for acetaldehyde (K m > 1 mM), and consequently their involvement in the metabolism of acetaldehyde is insignificant (Lundquist 1970; Lindros 1978). The main enzyme oxidizing acetaldehyde is aldehyde dehydrogenase (ALDH), which catalyzes the oxidation of acetaldehyde in the presence of nicotinamide-adenine dinucleotide (NAD) as follows: $$ C{H_3}CHO + NA{D^ + }\xrightarrow[{{H_2}O}]{{ALDH}}C{H_3}CO{O^ - } + NADH + {H^ + }. $$ Most of the acetaldehyde formed from ethanol is subsequently oxidized to acetate in liver.

Abstract: Two men with unusually high blood acetaldehyde levels of 750 and 2410 micrograms/dl presented only mild symptomatology. Their blood ethanol levels, 730 and 1121 mg/dl, were also extraordinarily high. However, liver function tests demonstrated no abnormalities. Language: en

Abstract: Until recently the alcohol dehydrogenase of Drosophila melanogaster was thought to act only in the first step of primary alcohol oxidation, producing an aldehyde. Instead, acetic acid is the main product of a two-step process. A rapid procedure was developed for the isolation and purification of two allozymes. The thermostability of the purified enzymes was found to be very different, t 1/2 at 35 degrees C, being 45 min and 130 min for ADH-F and ADH-71k respectively. The kinetic parameters of ethanol oxidation by the two purified allozymes were determined within physiological substrate and coenzyme ranges. The use of artificial electron acceptors has a notable influence on the ethanol oxidation: the apparent Michaelis constants increase; the oxidation rate with ADH-71k increases, whereas it decreases with ADH-F. Purified ADH is shown to be able to catalyze the oxidation of acetaldehyde solely in the presence of NAD+, and PMS and MTT as artificial electron acceptors. From the kinetic data the relative in vivo oxidation rates of ethanol by both ADH allozymes were calculated. ADH-F turned out to be somewhat less effective (30%-40%) than ADH-71k. The physiological consequences of these differences are discussed.

Abstract: 1. 1. Alcohol dehydrogenase (ADH) allozymes (FF, SF, SS) were purified to homogeneity from strains of Drosophila melanogaster using a new procedure. 2. 2. All allozymes displayed aldehyde dehydrogenase activity on cellulose (ALDH) acetate zymograms, corresponding to the ADH activity zones. 3. 3. Kinetic analyses with acetaldehyde as substrate revealed non-linear, biphasic Lineweaver-Burk plots giving two apparent Michaelis constants ( K m ) ranges for the allozymes of 1–10 μM and 0.1–1 mM. 4. 4. In contrast, kinetic analyses with ethanol as substrate gave results consistent with a single K m value of approximately 2 mM. 5. 5. At approx. 3 μM substrate concentration, the enzymes exhibited equivalent rates of dehydrogenase activity with either ethanol or acetaldehyde; whereas at a concentration of 10 mM, the ADHs exhibited approx. a 10-fold higher activity with ethanol as substrate. 6. 6. The specific activity of ADH-FF was 2–3 times higher than ADH-SS with both ethanol and acetaldehyde as dehydrogenase substrates. ADH and ALDH activities were inhibited by pyrazole, disulphiram and p -hydroxymercuribenzoate. 7. 7. Atomic absorption spectrometry confirmed the absence of zinc. 8. 8. The oxidation of 2-[ 13 C]-labelled ethanol by ADH allozymes in vitro was studied using nuclear magnetic resonance spectrometry. 9. 9. Acetaldehyde, its diol and acetate were detected within 20 min and monitored for 10 hr. 10. 10. The significance of these results for studies on ethanol metabolism in D. melanogaster is discussed.

Abstract: A rise in blood and liver acetaldehyde concentrations following ethanol loading (1.5 g/kg b.wt) was significantly reduced when rats were pretreated orally with taurine (0.5 g/kg), a potent in vitro activator of yeast aldehyde dehydrogenase. This taurine pretreatment produced a 4-fold increase in liver taurine content.