Composition of rat serum proteins under the effect of acetaldehyde and ethanol

Concentration and composition of rat serum proteins have been studied both under the isolated acetaldehyde effect and against a background of the action of acute and chronic intoxication by ethanol. Acetaldehyde evoked an increase in the concentration of the total serum proteins, the value of this parameter remaining unchanged under the ethanol effect. A comparison of ethanol and acetaldehyde effects gives ground to suppose that the quantitative redistribution of blood serum proteins which observed under ethanol intoxication is to a considerable extent a result of the acetaldehyde effect and is determined by aggregation of proteins.     

Effect of acetaldehyde on ethanol- and aldehyde-metabolising systems of the liver and brain of rats

Lately the mechanism of craving for alcohol has been related to the local level of brain acetaldehyde occurring in ethanol consumption and depending on the activities of the brain and liver ethanol and acetaldehyde-metabolizing systems. In this connection, we studied the effect of chronic acetaldehyde intoxication on the activities of alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), the microsomal ethanol oxidizing system (MEOS) and liver and brain catalase as well as ethanol and acetaldehyde levels in the blood. The results showed that the chronic acetaldehyde intoxication did not alter significantly the activities of liver ADH, MEOS and catalase as well as liver and brain ALDH. In parallel with this, the systemic acetaldehyde administration led to shortened time of ethanol narcosis and activation of catalase in the cerebellum and left hemisphere, which may indicate involvement of this enzyme into metabolic tolerance development.     

Infusions of acetaldehyde into the arcuate nucleus of the hypothalamus induce motor activity in rats

AimsThe hypothalamic arcuate nucleus (ARH) is one of the brain regions with the highest levels of catalase expression. Acetaldehyde, metabolized from ethanol in the CNS through the actions of catalase, has a role in the behavioral effects observed after ethanol administration. In previous studies acetaldehyde injected in the lateral ventricles or in the substantia nigra reticulata (SNR) mimicked the behavioral stimulant effects of centrally administered ethanol.Main methodsIn the present study we assessed the effects of acetaldehyde administered either into the ARH into a dorsal control or into the third ventricle on locomotion and rearing observed in 30 min sessions in an open field.Key findingsAcetaldehyde injected into the ARH induced horizontal locomotion and rearing for 20 min. In contrast, administration of acetaldehyde into a control site dorsal to the ARH did not have any effect on locomotion. Although acetaldehyde administration into the third ventricle also induced locomotion, the time course for the effect in this area was different from the time course following ARH injections. Acetaldehyde in the ARH produced a long lasting induction of locomotion, while with intraventricular injections the effects disappeared after 5 min.SignificanceThe present results are consistent with previous studies demonstrating that acetaldehyde is an active metabolite of ethanol, which can have locomotor stimulant properties when administered in the ventricular system of the brain or into specific brain nuclei. Some brain nuclei rich in catalase (i.e.; SNR and ARH) could be mediating some of the locomotor stimulant effects of ethanol through its conversion to acetaldehyde.     

Differential secretion of catecholamines and tetrahydroisoquinolines from the bovine adrenal medulla

Acetaldehyde, the primary metabolite of ethanol, condenses with endogenous amines to form tetrahydroisoquinoline derivatives which have been implicated in the behavioral and autonomic effects of alcohol. Because of difficulties encountered in the $\text{in}$$\text{vitro}$ synthesis of the tetrahydroisoquinolines derived from the condensation of acetaldehyde with epinephrine or norepinephrine, their “in tissue” biosynthesis in the isolated perfused bovine adrenal medulla was undertaken, and their mechanism of release investigated. When calcium was present in the perfusion medium, acetaldehyde evoked release of catecholamines as well as synthesis and release of their tetrahydroisoquinoline condensation products. In the absence of calcium in the perfusion medium, acetaldehyde induced the syntheis of tetrahydroisoquinolines but evoked the release of catecholamines only. The results indicate that the release of catecholamines and their tetrahydroisoquinoline derivatives can be uncoupled, and their differential secretion from the adrenal medulla achieved by altering the ionic composition of the extracellular fluid.     

Effect of acetaldehyde on Saccharomyces cerevisiae and Zymomonas mobilis subjected to environmental shocks

The lag phase of Saccharomyces cerevisiae subjected to a step increase in temperature or ethanol concentration was reduced by as much as 60% when acetaldehyde was added to the medium at concentrations less than 0.1 g/L. Maximum specific growth rates were also substantially increased. Even greater proportional reductions in lag time due to acetaldehyde addition were observed for ethanol-shocked cultures of Zymomonas mobilis. Acetaldehyde had no effect on S. cerevisiae cultures started from stationary phase inocula in the absence of environmental shock and its lag-reducing effects were greater in complex medium than in a defined synthetic medium. Acetaldehyde reacted strongly with the ingredients of complex culture media. It is proposed that the effect of added acetaldehyde may be to compensate for the inability of cells to maintain transmembrane acetaldehyde gradients following an environmental shock. (c) 1997 John Wiley & Sons, Inc.     

Ethanol and leucine oxidation--III. Leucine oxidation by rat heart in vitro

The activities of leucine aminotransferase (BCAT) and 2-oxoisocaproate dehydrogenase (OADH) were measured in rat heart in vitro. The effect upon these enzyme activities of both ethanol and acetaldehyde, administered either acutely or chronically, was determined. Enzyme activities were not significantly altered by either acetaldehyde or ethanol when given chronically. Ethanol administered acutely to rats decreased OADH activity but BCAT was unaffected. Acetaldehyde administered acutely did not alter significantly BCAT activity but significantly increased OADH activity.     

Effect of ethanol on protein synthesis in the tissues of various organs of guinea pigs

Long-term administration (for three months) of ethanol has been studied for its effect on the composition and synthesis of electrophoretic fractions of soluble proteins of the liver, brain, heart, kidneys and adrenals tissues in the guinea pigs. The obtained data permit supposing that the quantitative redistribution of the fractions under study as influenced by ethanol is due to their aggregation. Most of the studied tissues demonstrate a decrease in specific radioactivity of total proteins and 5 of 8-9 recorded electrophoretic fractions. Only one fraction in the heart and brain has been characterized by an increase of the protein synthesis level. The authors' results and data from literature make it possible to conclude that while analyzing pathogenesis of the chronic intoxication by ethanol and alcoholism the quantitative redistribution of soluble proteins and suppression of their synthesis in various tissues should be taken into account.     

Pharmacokinetics of ethanol and its metabolite, acetaldehyde, and fetolethality in the third-trimester pregnant guinea pig for oral administration of acute, multiple-dose ethanol

The pharmacokinetics of ethanol and its metabolite, acetaldehyde, were determined in the third-trimester pregnant guinea pig (56-59 days gestation) for oral intubation of four doses of 1 g ethanol/kg maternal body weight, administered at 1-h intervals. Animals (n = 4-7) were sacrificed at each of selected times during the 26-h study. Ethanol and acetaldehyde concentrations were determined by headspace gas-liquid chromatography. The maternal and fetal blood ethanol concentration-time curves were virtually superimposable, which indicated unimpeded bidirectional placental transfer of ethanol in the maternal-fetal unit. The blood and brain ethanol concentrations were similar in each of the maternal and fetal compartments during the study, which indicated rapid equilibrium distribution of ethanol. There was accumulation of ethanol in the amniotic fluid resulting in higher ethanol concentration compared with maternal and fetal blood during the elimination phase, which indicated that the amniotic fluid may serve as a reservoir for ethanol in utero. Acetaldehyde was measurable in all the biological fluids and tissues at concentrations that were at least 1,000-fold less than the respective ethanol concentrations and were variable. There was ethanol-induced fetolethality that was delayed and variable among animals, and was 55% at 23 h. At this time interval, the ethanol concentrations in maternal blood and brain, fetal brain, and amniotic fluid were 35- to 53-fold greater and the acetaldehyde concentrations in maternal blood and fetal brain were four- to five-fold higher in the animals with dead fetuses compared with the guinea pigs with live litters. These data indicated that decreased ethanol elimination from the maternal-fetal unit was related temporally to the fetolethality.     

Effect of chronic ethanol or acetaldehyde on hepatic alcohol and aldehyde dehydrogenases, aminotransferases and glutamate dehydrogenase

Ethanol or acetaldehyde orally administered (15% and 2% respectively in drinking water) to male Wistar rats for three months induced alterations in the main liver enzymes responsible for ethanol metabolism, aspartate and alanine aminotransferases and NAD glutamate dehydrogenase. Ethanol produced a significant decrease in the activity of soluble alcohol dehydrogenase, while acetaldehyde induced alterations both in soluble and mitochondrial aldehyde dehydrogenases: soluble activity was significantly higher than in the control and ethanol-treated groups, and mitochondrial activity was significantly diminished. Both soluble aspartate and alanine aminotransferases showed pronounced increases by the chronic effect of acetaldehyde, while mitochondrial activities were practically unchanged by the effect of ethanol or acetaldehyde. Mitochondrial NAD glutamate dehydrogenase showed a rise in its activity both by the effect of chronic ethanol and acetaldehyde consumption. The level of metabolites assayed in liver extracts showed marked differences between ethanol and acetaldehyde treatment which indicates that ethanol produced a remarkable increase in glutamate, aspartate and free ammonia together with marked decrease in pyruvate and 2-oxoglutarate concentrations. Acetaldehyde consumption induced a significant decrease in 2-oxoglutarate and pyruvate concentrations. These observations suggest that ethanol has an important effect on the urea cycle enzymes, while the effect of acetaldehyde contributes to the impairment of the citric acid cycle.     

Effect of ethanol on glutathione concentration in isolated hepatocytes.

1. Ethanol induces a decrease in GSH (reduced glutathione) concentration is isolated hepatocytes. Maximal effects appear at 20 mM-ethanol. The concentration-dependence of this decrease is paralleled by the concentration-dependence of the activity of alcohol dehydrogenase. 2. Pyrazole, a specific inhibitor of alcohol dehydrogenase, prevents the ethanol-induced GSH depletion. 3. Acetaldehyde, above 0.05 mM, also promotes a decrease in GSH concentration in hepatocytes. 4. Disulfiram (0.05 mM), an inhibitor of aldehyde dehydrogenase, potentiates the fall in GSH concentration caused by acetaldehyde. 5. The findings support the hypothesis that acetaldehyde is responsible for the depletion of GSH induced by ethanol. 6. Methionine prevents the effect of alcohol or acetaldehyde on GSH concentration in hepatocytes.     

Metabolic effects of acetaldehyde

Acetaldehyde, the toxic product of ethanol metabolism in the liver, covalently binds to a variety of proteins, thereby altering liver function and structure. Through its binding to tubulin, acetaldehyde decreases the polymerization of microtubules thereby impairing protein secretion and favouring their retention, with associated swelling of hepatocytes. Acetaldehyde adduct formation also impairs some enzyme activities. Either directly or through binding with GSH, acetaldehyde favours lipid peroxidation. Various mitochondrial functions are altered, particularly after chronic ethanol consumption which sensitizes the mitochondria to the toxic effects of acetaldehyde. In cultured myofibroblasts, acetaldehyde stimulates collagen production. The acetaldehyde-protein adducts stimulate the production of antibodies directed against the acetaldehyde epitope. This immune response may contribute to the aggravation or perpetuation of alcohol-induced liver damage. Some acetaldehyde effects, however, could conceivably be considered as beneficial, such as the stimulation of vascular prostacyclin release which may take part in the 'protective' effect of moderate ethanol consumption against some cardiovascular complications.     

乙醇与乙醛对心脏的影响及其可能机制的探讨

通过研究乙醇、乙醛对离体心脏和神经干的影响,探讨乙醇、乙醛对心脏作用的可能机制.用不同浓度的乙醇和乙醛处理牛蛙蛙心灌流标本和坐骨神经标本,用BL-420 系统对给药前后心脏的心率和振幅以及神经干最小刺激强度作记录.乙醇和乙醛可以引起神经兴奋性的改变从而影响神经冲动的传导,而且其影响具有明显的量效依赖关系,低浓度的乙醇和乙醛能使神经的兴奋性增加,高浓度则降低;乙醇对心脏的心率和振幅均有抑制作用,低浓度的乙醛对心脏心率和振幅有促进作用,高浓度的乙醛对心脏造成不可恢复的损伤.乙醇、乙醛对心脏的影响效果不同,但两者均可直接影响及通过神经而间接影响心脏的活动.     

乙醛在小鼠酒依赖性行为中的作用研究

乙醛为酒精代谢的中间产物,但其在酒依赖中的作用不清楚.通过条件化位置偏好(CPP)和条件化味觉偏好(CTP)试验,分析乙醛对小鼠乙醇依赖性行为的影响,研究乙醛在酒依赖中的作用.研究发现,经0.8%乙醇预处理7d后,小鼠训练8次则表现出对乙醇的条件化位置偏好(n=6,P<0.01),而经乙醛训练的小鼠则对乙醛无明显条件化偏好行为(n=6,P>0.05).当用0.8%乙醇、0.4%乙醛混合训练乙醇依赖性小鼠时,其位置偏好行为减弱(n=6,P<0.01).10%乙醇预处理的小鼠味觉偏好乙醇(n=6,P<0.01),而当乙醇中加入1%乙醛时,其味觉偏好现象减弱(n=6,P<0.01).1%乙醛训练7d后的小鼠不表现对乙醇的味觉偏好,但选择摄入乙醛及乙醇、乙醛混合溶液的量有所增加.结果表明乙醛在小鼠酒依赖行为中可能存在一定促进作用.     

Inhibition of acetaminophen activation by ethanol and acetaldehyde in liver microsomes

Mechanisms of the inhibitory effect of ethanol on acetaminophen hepatotoxicity are controversial. We studied the effects of ethanol and acetaldehyde, an oxidative metabolite of ethanol, on NADPH-dependent acetaminophen-glutathione conjugate production in liver microsomes. Ethanol at concentrations as low as 2mM prevented the conjugate production noncompetitively. Acetaldehyde also inhibited acetaminophen-glutathione conjugate production at concentrations as low as 0.1mM that is comparable with those observed in vivo after social drinking. Acetaldehyde may be involved in ethanol-induced inhibition of acetaminophen hepatotoxicity.     

Correction with formate of metabolic disorders in alcoholic intoxication

Formate was studied for its effect on the content of acetaldehyde, activity of the total aldehyde dehydrogenase, content of substrates of glycolysis and tricarbonic-cycle and pool of free amino acids of rat tissues during alcohol intoxication. The introduction of formate during the acute alcohol intoxication lowers the acetaldehyde content in the blood; the ethanol load being prolonged--it increases the activity of aldehyde dehydrogenase and normalizes the content of pyruvate, glutamate and malate in the liver and glutamate and oxaloacetate in the brain, that evidences for the correction of metabolic disturbances in the organism.     

The role of acetaldehyde and glycerol in the adaptation to ethanol stress of Saccharomyces cerevisiae and other yeasts

Ethanol inhibition is a commonly encountered stress condition during typical yeast fermentations and often results in reduced fermentation rates and production yields. While past studies have shown that acetaldehyde addition has a significant ameliorating effect on the growth of ethanol-stressed Saccharomyces cerevisiae , this study investigated the potential ameliorating effect of acetaldehyde on a wide range of ethanol-stressed yeasts. Acetaldehyde does not appear to be a universal ameliorating agent for yeasts exposed to ethanol stress. It is also shown that as a result of an ethanol stress, most yeasts rapidly produce glycerol as an alternative means of NAD⁺ regeneration rather than having a specific requirement for glycerol. The results strongly suggest that both ethanol and acetaldehyde exposure have a direct effect on the cellular NAD⁺/NADH ratio, which can manifest itself as modulations in glycerol production.     

The inhibition of human leukocyte elastase by basic pancreatic trypsin inhibitor

The effects of 30-min intravenous infusions of ethanol (about 50 mm blood concentration), acetaldehyde (about 100 μm blood concentration), and acetate (equimolar dose to acetaldehyde) were studied in normal and adrenalectomized rats. Blood glucose, plasma free fatty acids (FFA), plasma immunoreactive insulin, and glucagon and hepatic glycogen concentrations were measured. Ethanol itself in the presence of 4-methylpyrazole (4-MP) produced no marked changes in the parameters measured. Its infusion without 4-MP reduced plasma insulin by 35% in the normal rats, but not in the adrenalectomized rats, with no simultaneous changes in blood glucose. Acetaldehyde infusion produced hyperglycemia and relatively slight hyperinsulinemia in the normal rats, but not in the adrenalectomized rats. Equimolar acetate was not as potent a stimulator of glycogenolysis as acetaldehyde. Plasma FFA concentrations were markedly reduced by ethanol (without 4-MP), acetaldehyde and acetate both in the normal and adrenalectomized rats, but in the presence of 4-MP ethanol was without effect. The results indicate that metabolites of ethanol (mostly acetaldehyde) produced during ethanol oxidation in vivo are responsible for the stimulation of glycogenolysis through the release of catecholamines from the adrenal glands. The ethanol-induced decrease in plasma FFA is also attributable to the metabolites of ethanol, acetaldehyde having a more potent depressing action than acetate. The mode of inhibition of lipolysis is not related to hormonal factors.     

Ethanol infusion increases ANP and p21 gene expression in isolated perfused rat heart

Whether alcohol-induced heart failure is caused by a direct toxic effect of ethanol, metabolites, or whether it is a secondary result of neurohumoral, hormonal, or nutritional factors is not clear. To address this question a Langendorff retrograde coronary perfusion model of rat heart was used to study the effect of 0.5% (v/v) ethanol (n = 7) and 0.5 mM acetaldehyde (n = 9) on left ventricular expression of ANP, BNP, p53, p21, TNF-alpha,bax, bcl-2 as well as on DNA-fragmentation. Ethanol infusion of 150 min duration significantly induced both ANP and p21 mRNA expression of ventricular myocardium compared with hearts infused with vehicle (n = 8). Acetaldehyde did not exert any significant effects on any of the parameters studied, although the mean expression of TNF-alpha tended to be lower in the acetaldehyde-treated hearts than in control hearts. No evidence of increased DNA-fragmentation was found in ethanol or acetaldehyde treated groups. We conclude that ethanol per se is capable of inducing genes associated with hypertrophy and impaired function of the heart whereas a significant apoptosis is not involved in the initial phase of alcohol-induced cardiac injury.     

Cellular energy charge in the heart and liver of the rat. The effects of ethanol and acetaldehyde

The effects of ethanol and acetaldehyde upon adenine nucleotide concentrations in rat heart and liver were determined. Ethanol administered either acutely (8 g kg 0.73) or chronically (20% solution in drinking water for 21 d) significantly decreased ATP concentrations, adenylate energy charge (EC) and adenylate kinase mass action ratio (gamma AK) in liver but affected gamma AK only in heart. Acetaldehyde treatment elicited similar effects but of lesser magnitude.