Abstract: Phillips S.C. & Cragg B.G. 1982 Neuropathology a id Applied Neurobiology 8, 455–463 A change in susceptibility of rat cerebellar Purkinje cells to damage by acetaldehyde during fetal neonatal and adult life The sensitivity of rat cerebellar Purkinje cells to acetaldehyde during fetal, neonatal or adult life has been assessed by histological techniques. A pregnant female rat was exposed to ethanol vapour during the last 2 weeks of gestation while metabolism of acetaldehyde was blocked by injections of disulfiram (200mg/kg) on days E14, E16, E18 and E20. Purkinje cells were counted in the offspring 5 days after birth. The number of Purkinje cells in lobes I and VIII were 52% and 42% less than age matched controls. Smaller reductions were found in lobes V and X. The weight of the cerebellum was reduced by 42%. Neonatal rats received disulfiram (40mg) on the second day after birth and were exposed to ethanol vapour during daylight hours on the third and fourth days. Purkinje cells were counted at 5 days after birth, and losses similar to those described above were found. The weight of the cerebellum was reduced by 47%. Adult male rats were exposed to ethanol vapour for 2 weeks and given disulfiram (200mg/kg) on every second day. No reduction in cerebellar weight or loss of Purkinje cells was detected. When the dura overlying the cerebellum in adult rats was superfused with acetaldehyde solutions for 1 h, a 1–6 M solution caused degeneration whereas a 0–68 M solution did not. Thus the combination of high blood ethanol and acetaldehyde levels is damaging to perinatal Purkinje cells, whereas adult cells are resistant. We found the same ranking of susceptibility with ethanol alone (Philips & Cragg, 1982a and it was surprising that the cell losses with acetaldehyde were only marginally greater than those with ethanol alone, in view of the greater neurotoxicity of acetaldehyde during acute exposure (Phillips, 1981.

Abstract: The effects of alcohol on bone marrow are not well understood. We measured the influence of ethanol and its metabolite, acetaldehyde, on the in vitro proliferation of hematopoietic progenitor cells from mice and human beings. Colony formation by both early and late erythroid progenitor cells was suppressed by concentrations of ethanol (0.05 to 0.2 per cent) that are easily achieved in vivo. The corresponding suppressing concentration of acetaldehyde was 0.001 per cent. In contrast, suppression of granulocyte/macrophage progenitor cells required 3.0 per cent ethanol or 0.03 per cent acetaldehyde. Spleen colony formation by pluripotent stem cells was resistant to concentrations of ethanol and acetaldehyde that suppressed in vitro colony formation of committed myeloid and erythroid progenitor cells by 50 per cent. The suppression of both myeloid and erythroid colony formation was partially reversed by supplementing the cultures with folinic acid or pyridoxine. These data provide an explanation for the preferential suppression of erythropoiesis observed clinically in ethanol abuse. They also suggest that acetaldehyde has a role in ethanol-mediated bone-marrow suppression.

Abstract: The quantity of glycerol as principal by-product of the alcoholic fermentation depends to a large extent on the yeast strain. Different strains of Saccharomyces cerevisiae were found to form amounts of glycerol varying between 4.2 to 10.4 g/L. The formation of glycerol is regarded as a result of the competition between alcohol dehydrogenase and glycerol-3-phosphate dehydrogenase that compete for the reduced coenzyme NADH2. High and low glycerol forming yeast strains showed large differences in the activity of glycerol-3-phosphate dehydrogenase and only small variations in the activity of alcohol dehydrogenase. The total amount of glycerol formed was also influenced by amino acids. In thiamine deficient media a decrease in glycerol formation was observed. Experiments indicate a correlation between the formation of acetaldehyde and glycerol and the production of cell mass that may be of practical interest. Glycerol is by far the most important secondary product of fermentation. The glycerol content of wine may be of two different origins. A certain amount of glycerol is always formed by yeasts. Occasionally, glycerol is already present in the grape must, as has been observed by Mtihlberger and Grohmann (7). This glycerol is formed by Boyrytis cinerea, a fungus which frequently attacks grapes when they are produced in humid climates. The amount of glycerol formed by yeasts is generally assumed to be in the range of 1/10 or 1/15 of the alcohol formed (11). The formation of glycerol is not constant but depends on various factors. Early observations date back to the last century. Because of the sweet taste that is similar to glucose (11), a high content of glycerol may have a favorable effect on the taste of wines. Besides the yeast strain, such factors as oxygen, fermentation temperatures, and pH have been reported to influence the formation of glycerol. Within the "normal" range of conditions these factors are obviously not very important, particularly when the range of the pH is kept between 2.8 to 5.0. There is no doubt that the formation of glycerol does not only depend on the yeast strain, but also to a large extent on the composition of the fermentation medium. It is the purpose of this paper to show how environmental factors and characters of yeast strains influence the formation of glycerol during fermentation.

Abstract: In order to explain the mechanism for removing the astringency from persimmon fruit by high carbon dioxide treatment, we studied in vitro whether purified kaki-tannin, a kind of polymeric proanthocyanidin, reacts with acetaldehyde to become a gel under mild conditions or not.Kaki-tannin reacted with acetaldehyde in a relatively short time to become a gel in phosphate buffer at pH 6 to 8. Phosphate, malate and citrate accelerated the gel formation, whereas ethanol, ascorbate and Tricine buffer prevented it. Formaldehyde was more effective, and propylaldehyde was less effective than acetaldehyde in causing gelation.We suggest that the de-astringency is due to the insolubilization of kaki-tannin, which occurs by means of reacting with acetaldehyde produced in the fruit during high carbon dioxide treatment.

Abstract: Ingestion of a moderate dose of ethanol (0.8 g/kg) by volunteers prior to 4-h inhalation exposure to m-xylene (6.0 or 11.5 mmol/m3) caused marked alterations in xylene kinetics. After ethanol intake the blood xylene level rose about 1.5–2.0-fold and urinary methylhippuric acid excretion declined by about 50% suggesting that ethanol decreased the metabolic clearance of xylene by about one half during xylene inhalation. This effect was noticeable up until a few hours after completed xylene exposure. Urinary excretion of 2,4-xylenol, the minor m-xylene metabolite, was generally not decreased by ethanol and sometimes the reverse seemed to be the case. The disturbance of xylene kinetics can be hypothesized to be caused mainly by ethanol-mediated inhibition of microsomal metabolism. When four volunteers who ingested ethanol prior to m-xylene inhalation at the higher concentration were monitored for blood acetaldehyde, transiently raised levels were found without notable effects on ethanol elimination. This observation may explain why some individuals experienced dizziness and nausea during the combined ethanol-xylene exposure.

Abstract: High blood acetaldehyde levels in alcoholics after ethanol ingestion are due to reduced acetaldehyde oxidation rather than to an increased rate of its formation from ethanol. This is associated with low hepatic acetaldehyde dehydrogenase activity in alcoholic subjects and may represent a specific abnormality in them.

Abstract: Incubation of rat liver microsomes with acetaldehyde followed by reduction with borohydride of the Schiff bases formed leads to the formation of the N-ethyl derivatives of phosphatidylethanolamine and phosphatidylserine. Proof for this structure came from a comparison of these microsomal derivatives, and the nitrogenous bases derived therefrom by acid hydrolyses, with synthetic N-ethylphosphatidylethanolamine, N-ethylphosphatidylserine, N-ethylethanolamine, and N-ethylserine. Modification of membrane phospholipids by covalent binding of acetaldehyde to form Schiff bases may perturb some of the biochemical processes associated with membranes.

Abstract: Kinetic studies suggested the presence of several forms of NAD-dependent aldehyde dehydrogenase (ALDH) in rat brain. A subcellular distribution study showed that low- and high-Km activities with acetaldehyde as well as the substrate-specific enzyme succinate semialdehyde dehydrogenase were located mainly in the mitochondrial compartment. The low-Km activity was also present in the cytosol (less than 20%). The low-Km activity in the homogenate was only 10-15% of the total activity with acetaldehyde as the substrate. Two Km values were obtained with both acetaldehyde (0.2 and 2000 microM) and 3,4-dihydroxyphenylacetaldehyde (DOPAL) (0.3 and 31 microM), and one Km value with succinate semialdehyde (5 microM). The main part of the aldehyde dehydrogenase activities with acetaldehyde, DOPAL, and succinate semialdehyde, but only little activity of the marker enzyme for the outer membrane (monoamine oxidase, MAO), was released from a purified mitochondrial fraction subjected to sonication. Only small amounts of the ALDH activities were released from mitochondria subjected to swelling in a hypotonic buffer, whereas the main part of the marker enzyme for the intermembrane space (adenylate kinase) was released. These results indicate that the ALDH activities with acetaldehyde, DOPAL and succinate semialdehyde are located in the matrix compartment. The low-Km activity with acetaldehyde and DOPAL, but not the high-Km activities and succinate semialdehyde dehydrogenase, was markedly stimulated by Mg2+ and Ca2+ in phosphate buffer. The low- and high-Km activities with acetaldehyde showed different pH optima in pyrophosphate buffer.

Abstract: Alcohol inhibits the secretion of protein from the liver. Chronic abuse results in intrahepatic accumulation of export-type proteins and decreased plasma levels. These effects appear to be mediated by acetaldehyde, an oxidation product of ethanol. Acetaldehyde is capable of interfering with the assembly of microtubules, a component of the cytoskeleton, the integrity of which is required for normal secretion. Protein retention and cytoskeletal alterations may contribute to manifestations of alcoholic liver disease, such as hepatomegaly, ballooning of the hepatocyte, portal hypertension, and development of Mallory bodies.

Abstract: The photoassisted reduction or aqueous carbon dioxide was carried out in the presence of suspensions of powdered strontium titanate, surface treated with various transition metal oxide additives, using either high-pressure mercury lamps or sunlight as the energy source. The organic products observed included formic acid, formaldehyde, methanol, acetaldehyde and ethanol.

Abstract: In recent reports it has been indicated that acute and chronic ethanol treatments affect the central dopaminergic system. In particular, after acute ethanol administration it has been detected an increase of dopamine (DA) turnover measured as dihydroxyphenylacetic acid (DOPAC) content in rat corpus striatum. In order to verify the correlation between these neuronal events and the metabolism of ethanol, we measured striatal DA activity after different experimental manipulations of liver function. Ethanol metabolic rate has been stimulated by administering phenobarbital sodium, while liver ethanol metabolism was decreased with a subtotal hepatectomy. In these conditions we found a shift to the left of the time curve for DOPAC levels and a significant reduction of the peak of DOPAC increase respectively. In this paper we report that acetaldehyde induces modifications of the striatal DOPAC content, which become significant after a shorter latency period in comparison with the acute ethanol injection. Our data suggest the hypothesis that the neurochemical effects of ethanol may be mediated by the formation of specific metabolic products.

Abstract: Infection is a major cause of morbidity and mortality in chronic alcoholics and may be attributable to altered lymphocyte function. To evaluate this possibility, the effects of physiologic concentrations of ethanol (ETH) and its metabolites, acetaldehyde (ACH) and acetate (ACT), were studied using in vitro mononuclear cell cultures prepared from normal human donors. ETH depressed DNA synthesis induced by both phytohemagglutinin-M(PHA) and Concanavalin A (Con A). ACH significantly impaired Con A and PHA stimulated lymphocyte DNA synthesis. Con A and PHA induced blastogenesis was also significantly reduced by the in vitro addition of ACT. Spontaneous lymphocyte transformation in these three-day cultures was not affected by ethanol but was decreased by the addition of high dose acetate and acetaldehyde. Lymphocyte response to candida and trichophyton antigens was significantly depressed by ETH and its metabolites. Monocyte depletion by adherence had no effect on these results. Treatment of lymphocytes with ETH, ACH or ACT did not change T cell binding of sheep erythrocytes or B cell expression of surface immunoglobulin or receptor sites for complement. It is concluded that both ethanol and its metabolites in physiologic concentrations significantly inhibited lymphocyte function without altering surface markers.

Abstract: The pathogenesis of the FAS, particularly the characteristic IUGR, may be due in part to ethanol-related placental injury. Ethanol and/ or acetaldehyde may impair placental transfer of nutrients essential for growth, e.g., amino acids. Such restriction could occur regardless of maternal nutritional status: selective fetal malnutrition. Impairment of placental nutrient transport at critical phases of fetal organogenesis could compound any direct fetotoxic effects of ethanol or acetaldehyde. The effect of ethanol upon human placental hormone synthesis and transport of vitamins, minerals, glucose, and nucleic acid precursors awaits further investigation. Similarly, potential interactions between ethanol and other xenobiotics commonly abused by alcoholics require clarification.

Abstract: Soybean (Glycine max L. var. Wilkin) nodules contain acetaldehyde and ethanol. The cytosol of soybean and other legume nodules contains pyruvic decarboxylase (EC 4.1.1.1) and alcohol dehydrogenase (EC 1.1.1.1). Some of the properties of these enzymes from soybean nodules are described. Their presence indicates that in the microaerobic nodule cytosol some carbohydrate is metabolized by fermentative pathways like those in the roots of flood-tolerant plants.

Abstract: Purified preparations of rat liver microsomes consist of flat discoid structures, presumably vesicles. They catalyze oxidation of ethanol to acetaldehyde in the absence of alcohol dehydrogenase and catalase with a specific activity of 1.4-53 nmol acetaldehyde formed min−1 (nmol cytochrome P-450)−1. The D(V/ K) isotope effect of this microsomal ethanol-oxidizing system was 1.15. This value is clearly different from those of alcohol dehydrogenase (3.0) and catalase (1.9). Particulate aldehyde dehydrogenases present in the preparation are active at unphysiologically high concentrations of aldehyde. Coincidently, the activity of the microsomal ethanol- oxidizing system, was well as the D(V/K) isotope effect associated with it, was increased significantly. This observation confirms the enzymic nature of the reaction studied. In microsomes washed once in KCI, ethanol oxidation was catalyzed mainly by catalase, but also by the microsomal ethanol-oxidizing system, as judged from the D(V / K) isotope effect upon the net reaction. In the presence of sodium azide alcohol dehydrogenase activity could be demonstrated. In hepatocytes from rat or pig, 4-methyl pyrazole at high concentrations reduced the rate of ethanol oxidation to 3-10%. The D(V/K) isotope effect upon the residual ethanol oxidation reflected activities of both catalase and the microsomal ethanol- oxidizing system. The activity of this latter system was inhibited by 4-methyl pyrazole competitively with ethanol, Ki= 5.7 mM. When this inhibition is taken into account, the uninhibited membrane system activity in these cells amount to maximally 10% of the rate of ethanol oxidation in the absence of inhibitor.

Abstract: Acetaldehyde-dependent chemiluminescence has been found to be a sensitive technique for the study of superoxide and hydrogen peroxide formation in beef heart mitochondria. The system responds to ATP and antimycin A with increased emission intensities and to ADP and rotenone with decreased intensities, indicating that the chemiluminescence reflects the energy status of the mitochondrion. These effects are based on the ability of acetaldehyde to react with superoxide and hydrogen peroxide to form metastable intermediates which decay spontaneously with the emission of light. Additionally, these intermediates can react with cyanide to give alternative products which can also decay with the emission of light, the cyanide-evokable chemiluminescence. The interaction of acetaldehyde with mitochondria is complex because acetaldehyde can serve as a hydrogen source for NADH and as an inhibitor (at high concentration) of electron transport, and appears to be a reducing agent for a heat-stable site that autoxidatively generates HOOH from O2−·. Inasmuch as acetaldehyde is a metabolite of ethanol, this broad spectrum of reactivity may play a role in the hepatic and cardiac toxicity that is associated with alcoholism. The heat-stable site that generates HOOH from O2−· has been studied further and appears to contain vicinal dithiol which is primarily responsible for the cyanide-evokable chemiluminescence.