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PubMedDate not supplied

Acetaldehyde-reinforcing effects: differences in low-alcohol-drinking (UChA) and high-alcohol-drinking (UChB) rats.

It has been suggested that acetaldehyde has a biphasic effect on voluntary alcohol consumption. At low brain concentration, it might exert reinforcing effects, whereas high acetaldehyde levels would be predominantly aversive. The objective of the current study was to compare the effect of an intraperitoneal dose of acetaldehyde (50 mg/kg) in high-alcohol-drinking (UChB) and low-alcohol-drinking (UChA) rat lines, which differ in the activity of the brain mitochondrial class 2 aldehyde dehydrogenase (ALDH2) as a consequence of differences in their ALDH2 genotypes. A classical place-conditioning procedure was used to determine the reinforcing or aversive (or both) effects of acetaldehyde in ethanol-naive UChB and UChA rats. Environmental cues were paired with an intraperitoneal 50-mg/kg injection of acetaldehyde. On 10 consecutive days, each rat received one place conditioning per day; the acetaldehyde-pairing was alternated with saline-pairing. Results showed that conditioning with the 50-mg/kg dose of acetaldehyde induced place preference in UChB rats and place aversion in UChA rats. In a second experiment, UChB and UChA rats, pretested for ethanol preference, were injected with one 50-mg/kg dose of acetaldehyde or saline and tested for their voluntary ethanol consumption during 4 weeks. Results showed that the acetaldehyde dose induced a persistent and long-lasting enhancement of ethanol intake in UChB rats, but not in UChA rats. These results, together with the finding that after administration of a 50-mg/kg dose of acetaldehyde cerebral venous blood acetaldehyde levels in UChA rats were consistently higher than levels in UChB rats, support the suggestion that differential acetaldehyde levels, differential brain ALDH2 activity, or both were responsible for the different effects of acetaldehyde in the two rat lines.

Acetaldehyde↗
PubMed1999

Generation of acetate and production of ethyl-lysine in the reaction of acetaldehyde plus serum albumin.

We report that incubation of acetaldehyde with bovine serum albumin results in the generation of acetate in a reaction that is directly proportional to the levels of albumin and exponentially dependent on the concentration of acetaldehyde. Both reactants need to be present for acetate to be formed. The oxidation of acetaldehyde into acetate requires that a reduced product also be generated in the reaction. It was hypothesized that, at high concentrations, acetaldehyde itself may reduce the Schiff bases formed in the reaction of a second molecule of acetaldehyde with amino groups in the protein, resulting in the generation of ethyl-lysine moieties. Incubation of acetaldehyde (240 mM) with bovine serum albumin was found to generate ethyl-lysine moieties as determined by a specific monoclonal antibody. Immunization of rabbits with products of the reaction of bovine serum albumin with acetaldehyde led to the generation of antibodies that reacted to reduced adducts formed in the reaction of acetaldehyde and proteins in the presence of sodium cyanoborohydride. However, the generation of acetate from acetaldehyde plus albumin was 60-fold greater than could be explained by the reduction of Schiff bases, as determined by the maximal incorporation of [14C]-acetaldehyde into an acid-precipitable protein fraction. Thus, other mechanisms to generate acetate also occur. The present findings provide an explanation for earlier reports that acetaldehyde adducts formed under "nonreducing" conditions generate antibodies that recognize reduced acetaldehyde protein adducts. However, the mechanism by which the bulk of acetate is generated in the reaction of acetaldehyde and bovine serum albumin remains to be elucidated.

Acetaldehyde↗
PubMed1994

Studies of the oxidation of ethanol to acetaldehyde by oxyhemoglobin using fluorigenic high-performance liquid chromatography.

We noted a rise in acetaldehyde levels in clinical samples of venous whole blood containing ethanol that did not occur in samples from teetotalers. Experiments were performed to define the mechanism involved in acetaldehyde production. The addition of 0.10% ethanol to whole blood produced an immediate increase in acetaldehyde due to acetaldehyde in the stock solution followed by a subsequent increase that became statistically significant by 48 hr. Separation of blood into components documented that the increase in acetaldehyde was associated with the red cell but not plasma fraction. Incubation of isolated hemoglobin with ethanol produced a rise in acetaldehyde levels. Incubation of oxygenated whole blood with ethanol produced a linear increase in acetaldehyde, whereas nitrogen-exposed blood produced no increase. The rise of acetaldehyde in the presence of ethanol was dependent on the concentration of oxygenated hemoglobin A0. Addition of inhibitors of catalase, alcohol dehydrogenase, and glycolytic enzymes (aminotriazole, azide, pyrazole, sodium fluoride, sodium citrate, and iodoacetate) did not inhibit the rise of acetaldehyde, but addition of the hemoglobin ligand cyanide abolished the rise in acetaldehyde. Kinetic analysis with oxygenated whole blood plus inhibitors revealed a Km of 2.5 mM and Vmax of 1.42 microM/min. We conclude that oxyhemoglobin contributes to the metabolism of ethanol to acetaldehyde. These findings may explain in part the high levels of acetaldehyde found in red cells compared with plasma. The results also have implications for the optimum storage of blood samples for acetaldehyde analysis.

Acetaldehyde↗
PubMed1996

High intracolonic acetaldehyde values produced by a bacteriocolonic pathway for ethanol oxidation in piglets.

BACKGROUND: Human colonic contents and many colonic microbes produce considerable amounts of acetaldehyde from ethanol in vitro. AIMS: To examine in piglets if acetaldehyde is produced in the colon also in vivo, and if so, what is the fate of intracolonically formed acetaldehyde. ANIMALS: Seventeen native, non-fasted female piglets (20-25 kg) were used. METHODS: Six piglets received either 1.5 g/kg bw or 2.5 g/kg bw of ethanol intravenously. In seven piglets, 0.7 g or 1.75 g of ethanol/kg bw was administered intravenously, followed by a subsequent intragastric ethanol infusion of 1.8 g/kg bw and 4.5 g/kg bw, respectively. The samples of colonic contents for the assessment of ethanol and acetaldehyde concentrations were obtained up to seven hours. In four additional piglets, the intracolonic values of ethanol, acetaldehyde, and acetate were observed for 60 minutes after an intracolonic infusion of acetaldehyde solution. RESULTS: A raised intracolonic, endogenous acetaldehyde concentration (mean (SEM); 36 (9) microM) was found in all piglets before ethanol infusion. After the infusion of ethanol, intracolonic ethanol and acetaldehyde values increased in parallel, reaching the peak values 57 (4) mM of ethanol and 271 (20) microM of acetaldehyde in the group that received the highest dose of ethanol. A positive correlation (r = 0.45; p < 0.001) was found between intracolonic ethanol and acetaldehyde values. Acetaldehyde administered intracolonically was mainly metabolised to acetate but also to ethanol in the colon. CONCLUSIONS: Significant endogenous intracolonic acetaldehyde values can be found in the normal porcine colon. Furthermore, our results suggest the existence of a bacteriocolonic pathway for ethanol oxidation. Increased amounts of acetaldehyde are formed intracolonically from ingested ethanol by this pathway.

Acetaldehyde↗
PubMed1995

Measuring and reporting the concentration of acetaldehyde in human breath.

Most of the acetaldehyde generated during the metabolism of ethanol becomes tightly bound to endogenous molecules such as haemoglobin, amino acids and certain phospholipids. Free acetaldehyde passes the blood-brain barrier and traces of this toxic metabolite are excreted through the lungs and can be detected in the expired air. The blood/air partition coefficient of acetaldehyde at 34 degrees C, the average temperature of end-expired air, is about 190:1. Because of various problems associated with measuring acetaldehyde in blood samples, several research groups have instead investigated the analysis of acetaldehyde in breath which offers an indirect and alternative approach for clinical and research purposes. However, care is needed when interpreting the results of breath acetaldehyde measurements, because of the possibility of local formation from microflora inhabiting the upper airways and mouth. The concentration of acetaldehyde exhaled in breath after drinking alcohol demonstrates large inter-individual differences depending on various genetic (racial) and environmental factors. Moreover, acetaldehyde is an endogenous metabolite and even without drinking any alcohol the concentrations expelled in breath span from 0.2 to 0.6 nmol/l, with higher levels observed in smokers and abstinent alcoholics. Breath acetaldehyde concentration reached between 5 and 50 nmol/l in European subjects who drank a moderate dose of ethanol (0.4-0.8 g/kg), with the highest values seen in smokers. The concentration of breath acetaldehyde in Japanese subjects after drinking alcohol reached between 200 and 500 nmol/l at the peak. These much higher levels follow because a large proportion of Orientals (40-50%) inherit an inactive form of the low Km mitochondrial isoenzyme of aldehyde dehydrogenase (ALDH2). The highest concentration of breath acetaldehyde were seen in healthy Caucasians who drank a small dose of alcohol (0.25 g/kg) after taking the alcohol-sensitizing drug calcium carbimide, which blocks the action of ALDH isozymes. During the most intense acetaldehyde-flush reaction, breath acetaldehyde reached between 200 and 1300 nmol/l, but even these abnormally high concentrations did not interfere with the analysis of ethanol in breath by means of non-specific infrared analysers currently used in many countries for testing drinking drivers.

Acetaldehyde↗
PubMed2005

Early response of alpha2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-beta independent.

Acetaldehyde is fibrogenic and induces the expression of type I collagen genes in hepatic stellate cells. Some of these acetaldehyde-dependent events are mediated by H(2)O(2) and thus establish a direct connection between oxidative stress and collagen upregulation. We localized to the -378 to -183 region of the alpha2(I) collagen (COL1A2) promoter an acetaldehyde-responsive element (AcRE) functional in human hepatic stellate cells (HHSCs) and investigated molecular mechanisms whereby acetaldehyde stimulates and modulates its transcriptional activity. Because the AcRE co-localized with a previously described transforming growth factor beta (TGF-beta)1-responsive element, and both acetaldehyde and this cytokine induce their effects through H(2)O(2), we investigated whether all fibrogenic actions of acetaldehyde were mediated by this cytokine. Here we show that acetaldehyde-induced COL1A2 upregulation in HHSCs recognizes two distinct but overlapping early and late stages that last from 1 to 6 hours and from 6 to 24 hours, respectively. We present several lines of evidence to show that early acetaldehyde-mediated events are independent of TGF-beta1. These include significant time-course differences in the expression of COL1A2 and TGF-beta1 mRNAs and inability of neutralizing antibodies to TGF-beta1 to inhibit acetaldehyde-dependent collagen gene transcription and Smad 3 phosphorylation. We also show that although acetaldehyde-dependent upregulation of collagen was PI3K dependent, that of TGF-beta1 was PI3K independent. In conclusion, acetaldehyde-dependent mechanisms involved in COL1A2 upregulation are similar, but not identical, to those of TGF-beta1. We suggest that early acetaldehyde-dependent events induce the late expression of TGF-beta1 and create an H(2)O(2)-dependent autocrine loop that may sustain and amplify the fibrogenic response of this alcohol metabolite.

Acetaldehyde↗
PubMed1996

Long-term ethanol administration alters the degradation of acetaldehyde adducts by liver endothelial cells.

Previous reports have shown that long-term ethanol administration alters receptor-mediated endocytosis (RME) of a variety of macromolecules by liver endothelial cells (LEC). Acetaldehyde is the major metabolic product of ethanol metabolism and has been shown to bind to proteins to form adducts. In this study, the level of protein modification by acetaldehyde necessary for the uptake and degradation of acetaldehyde-modified proteins by LEC was investigated. Bovine serum albumin (BSA) acetaldehyde adducts were prepared by incubation of albumin with acetaldehyde at 100 mmol/L for 1 hour at 37 degrees C, and 1 mmol/L or 0.2 mmol/L for 5 days at 37 degrees C. In situ liver perfusion in the presence of these adducts resulted in the degradation of 107 +/- 10.02 microg, 69.82 +/- 5 microg, and 2.5 +/- 0.42 microg of acetaldehyde-adducted albumin, respectively, during a 4-hour period. These values were decreased by 53%, 67%, and nearly 100%, respectively, in livers from ethanol-fed rats. Additionally, modification of protein with 1 mmol/L of acetaldehyde for different periods of time and/or pH altered the amount of 14C-acetaldehyde binding, but no significant changes in degradation were observed. Finally, an excess of formaldehyde-modified albumin totally inhibited the degradation of acetaldehyde adducts, suggesting that they use the same receptor. These data show that acetaldehyde-modified proteins may be taken up and degraded by the scavenger receptor on LEC. This uptake and degradation are dependent on the extent modification of the protein by acetaldehyde, and long-term ethanol consumption decreases the degradation of acetaldehyde-protein adducts.

Acetaldehyde↗
PubMed1988

Effects of acetaldehyde on human red cell metabolism: evidence for the formation of enzyme inhibitors.

Since red cells transport and metabolize acetaldehyde in vivo, the effects of acetaldehyde on human red cell enzyme activities were studied. Incubation of intact red cells or undiluted red cell lysates at 37 degrees C for 4 h with 1-10 mmol/l acetaldehyde decreased only GOT, GPT and aldolase activities among the 26 enzymes tested. No inhibition occurred at 4 degrees C or when acetaldehyde was incubated with dilute hemolysates. Incubation of lysates with other reducing substrates or with acetate inhibited aldolase but not GOT or GPT. Preincubation of lysates with cyanate or fluoride markedly decreased acetaldehyde-mediated transaminase inhibition but not aldolase inhibition. Addition of pyridoxal phosphate, the vitamin B6 transaminase coenzyme, to GOT and GPT assay mixes did not reverse acetaldehyde-mediated transaminase inhibition. These findings suggest that acetaldehyde-mediated aldolase inhibition results from oxidation of acetaldehyde while transaminase inhibition results from nonoxidative acetaldehyde metabolism. When 100-200 mumol/l acetaldehyde is added to lysates at 2-h intervals and when lysates are incubated with ethanol, alcohol dehydrogenase and an NAD-regenerating system, enzyme inhibition occurs at acetaldehyde levels approaching those seen in vivo. Thus, the role of acetaldehyde-mediated enzyme inhibition in the toxicity of alcohol abuse warrants further study.

Acetaldehyde↗
PubMed1986

Decreased extractability of DNA from proteins in the rat nasal mucosa after acetaldehyde exposure.

Acetaldehyde and formaldehyde have been found to induce nasal cancer in two species of rodents. To understand the mechanism of carcinogenesis by acetaldehyde, studies were carried out to determine whether acetaldehyde can react with DNA in target tissues of the rat nasal cavity. When fresh homogenates of the nasal respiratory mucosa were incubated with acetaldehyde (distilled under N2) at concentrations of 10, 100, or 500 mM, followed by solubilization and extraction with a strongly denaturing aqueous-immiscible organic solvent mixture, a decrease was observed in the amount of DNA partitioned into the aqueous phase at the two higher acetaldehyde concentrations. The absent DNA was recovered from the interfacial layer by proteolytic digestion. Similarly, incubation of calf thymus nucleohistones with acetaldehyde (100, 300, Similarly, incubation of calf thymus nucleohistones with acetaldehyde (100, 300, or 1000 mM) or with formaldehyde (10, 30, or 100 mM) followed by precipitation of the DNA with H2SO4 and analysis of the supernatants by sodium dodecyl sulfate-polyacrylamide gel electrophoresis resulted in concentration-dependent decreases in the quantities of histone proteins released from the DNA. These results indicate that acetaldehyde as well as formaldehyde can form DNA-protein crosslinks in vitro. A single 6-hr exposure of male Fischer-344 rats to acetaldehyde (100, 300, 1000, or 3000 ppm) resulted in a significant increase relative to air-exposed controls in the percent interfacial DNA from the nasal respiratory mucosa at concentrations equal to or greater than 1000 ppm. No increase in the interfacial DNA from the olfactory mucosa was detected after a single 6-hr exposure (1000 or 3000 ppm), but a significant increase was found in rats hr/day for 5 days) to acetaldehyde (1000 ppm). Thus, evidence has been obtained hr/day for 5 days) to acetaldehyde (1000 ppm). Thus, evidence has been obtained for the formation of DNA-protein crosslinks by acetaldehyde in target tissues of the rat nasal cavity at concentrations similar to those that induced nasal cancer.

Acetaldehyde↗
PubMed2004

Genetic polymorphism in ethanol metabolism: acetaldehyde contribution to alcohol abuse and alcoholism.

Acetaldehyde, the first product of ethanol metabolism, has been speculated to be involved in many pharmacological and behavioral effects of ethanol. In particular, acetaldehyde has been suggested to contribute to alcohol abuse and alcoholism. In the present paper, we review current data on the role of acetaldehyde and ethanol metabolism in alcohol consumption and abuse. Ethanol metabolism involves several enzymes. Whereas alcohol dehydrogenase metabolizes the bulk of ethanol within the liver, other enzymes, such as cytochrome P4502E1 and catalase, also contributes to the production of acetaldehyde from ethanol oxidation. In turn, acetaldehyde is metabolized by the enzyme aldehyde dehydrogenase. In animal studies, acetaldehyde is mainly reinforcing particularly when injected directly into the brain. In humans, genetic polymorphisms of the enzymes alcohol dehydrogenase and aldehyde dehydrogenase are also associated with alcohol drinking habits and the incidence of alcohol abuse. From these human genetic studies, it has been concluded that blood acetaldehyde accumulation induces unpleasant effects that prevent further alcohol drinking. It is therefore speculated that acetaldehyde exerts opposite hedonic effects depending on the localization of its accumulation. In the periphery, acetaldehyde is primarily aversive, whereas brain acetaldehyde is mainly reinforcing. However, the peripheral effects of acetaldehyde might also be dependent upon its peak blood concentrations and its rate of accumulation, with a narrow range of blood acetaldehyde concentrations being reinforcing.

Acetaldehyde↗
PubMed2001

4-Methylpyrazole decreases salivary acetaldehyde levels in aldh2-deficient subjects but not in subjects with normal aldh2.

BACKGROUND: Carcinogenic acetaldehyde is produced from ethanol locally in the upper digestive tract via alcohol dehydrogenases (ADHs) of oral microbes, mucosal cells, and salivary glands. Acetaldehyde is further oxidized into less harmful acetate mainly by the aldehyde dehydrogenase-2 (ALDH2) enzyme. ALDH2-deficiency increases salivary acetaldehyde levels and the risk for upper digestive tract cancer in heavy alcohol drinkers. 4-methylpyrazole (4-MP) is an ADH-inhibitor which could reduce the local production of acetaldehyde from ethanol in the saliva. METHODS: Five ALDH2-deficient subjects and six subjects with normal ALDH2 ingested a moderate dose of alcohol (0.4 g/kg of body weight), whereafter their salivary acetaldehyde levels, heart rate, skin temperature, and blood pressure were followed for up to four hours. Blood acetaldehyde and ethanol levels were determined at 60 min. The experiment was repeated after a week. Two hours before the second study day, the volunteers received 4-MP, 10-15 mg/kg of body weight orally. RESULTS: Total ethanol elimination rate decreased with 4-MP by 38-46% in all subjects. 4-MP also reduced blood acetaldehyde levels and suppressed the cardiocirculatory responses of the ALDH2-deficient volunteers. In addition, salivary acetaldehyde production in ALDH2-deficient subjects was significantly reduced when correlated with salivary ethanol levels. On the contrary, 4-MP did not have any effect on salivary or blood acetaldehyde levels in subjects with normal ALDH2. CONCLUSIONS: A single dose of 4-MP before ethanol ingestion reduces ethanol elimination rate, the flushing reaction, and both blood and salivary acetaldehyde levels in ALDH2-deficient subjects but not in subjects with the normal ALDH2 genotype. These results suggest that the role of oral mucosal and glandular ADHs in salivary acetaldehyde production is minimal and support earlier findings indicating that salivary acetaldehyde production is mainly of microbial origin in subjects with normal ALDH2.

Acetaldehyde↗
PubMed2002

Airway obstruction induced by inhaled acetaldehyde in asthma: repeatability relationship to adenosine 5'-monophosphate responsiveness.

Inhaled acetaldehyde and adenosine 5'-monophosphate (AMP) cause bronchoconstriction in asthmatics by a mechanism believed to involve histamine release from airway mast cells. This study investigates the repeatability of the acetaldehyde challenge and the relationship between airway responsiveness to acetaldehyde and AMP. To this end, we examined the effect of inhaled acetaldehyde on airway tone in comparison with either methacholine or AMP in 16 asthmatics. Furthermore, the repeatability of the acetaldehyde challenge was assessed in 14 subjects with mild asthma. The response to each bronchoconstrictor agent was measured by the PC20 (provocative concentration required to produce a 20% fall in FEV1). The geometric mean (range) PC20 values were 3.1 mmol/l (0.5-46.0 mmol/l) for methacholine, 883.1 mmol/l (190.7-1816.1 mmol/l) for acetaldehyde, and 50.1 mmol/l (3.2-1152.1 mmol/l) for AMP. Thus, acetaldehyde was 18-fold less potent than AMP in causing bronchoconstriction. A similar correlation was observed between PC20 acetaldehyde and either PC20 AMP (r = 0.58, p = 0.02) or PC20 methacholine (r = 0.56, p = 0.02). The challenge procedure with acetaldehyde was moderately repeatable (coefficient of repeatability = +/- 1.4 doubling concentrations, intraclass correlation coefficient = 0.64). We conclude that inhaled acetaldehyde is less potent than AMP in causing bronchoconstriction in asthma, and that the response to inhaled acetaldehyde is repeatable. Furthermore, the present data lends indirect support to the suggestion that acetaldehyde responsiveness and AMP responsiveness are not identifying the same alterations in the airways.

Acetaldehyde↗
PubMed1987

Acetaldehyde increases collagen gene transcription in cultured human fibroblasts.

Acetaldehyde, the first metabolite of ethanol, mediates many of the biological effects of ethanol. We have previously shown that acetaldehyde, but not ethanol, stimulates collagen production in cultured human fibroblasts (Holt, K., Bennett, M., and Chojkier, M. (1984) Hepatology 4, 843-848). Here, we examined the effects of acetaldehyde on collagen gene expression. Confluent human fetal fibroblasts were incubated for up to 4 h in the presence of ascorbate (0.2 mM) alone or with the addition of either ethanol (12 mM) or acetaldehyde (200 microM). Acetaldehyde induced the production of collagen (up to 2.5-fold) and had a small inhibitory effect on procollagen secretion (-20%). The steady-state levels of mRNAs were measured by hybridizing total cellular RNA to specific cDNA probes at high stringency. Acetaldehyde increased the steady-state level of collagen alpha 1(I) and collagen alpha 2(I) mRNAs about 3-fold and had small effects on beta-actin mRNA (+50%) and collagenase mRNA (-50%). Northern blots revealed that the RNAs were intact and that acetaldehyde preferentially increased the abundance of the longer of the two collagen alpha 1(I) transcripts. Acetaldehyde increased both collagen alpha 1(I) and collagen alpha 1(III) transcriptional activity by 2.5-fold and had small effects on beta-actin and collagenase gene transcription. The increase in both collagen production and collagen mRNA levels induced by acetaldehyde was blocked by methylene blue, a scavenger of reducing equivalents. These data indicate that reducing equivalents, which enhance the formation and stability of acetaldehyde-protein adducts, may be required for acetaldehyde-stimulated collagen production. Thus, this study suggests that acetaldehyde increases collagen production by increasing collagen gene transcription in cultured human fibroblasts.

Acetaldehyde↗
PubMed1989

High levels of acetaldehyde in nonalcoholic liver injury after threonine or ethanol administration.

Acetaldehyde, a product of ethanol oxidation which forms adducts with proteins, has been incriminated in the pathogenesis of alcoholic liver injury. High serum antibody titers against acetaldehyde-protein adducts have been found not only in alcoholics but also in patients with nonalcoholic liver disease, suggesting a contribution of acetaldehyde derived from sources other than exogenous ethanol. To investigate the effect of liver injury on the removal and the production of acetaldehyde, we produced fibrosis and cirrhosis (by chronic administration of carbon tetrachloride) and fatty liver (with very small doses of dimethylnitrosamine) in rats. Endogenous blood acetaldehyde levels increased by 38% in rats with severe liver injury (p less than 0.005), but not significantly in rats with fatty liver. However, an i.v. load of threonine (a physiological source of acetaldehyde), in amounts equivalent to the daily intake of this amino acid, increased blood and hepatic acetaldehyde levels in the rats with both types of liver injury more than in controls. Threonine dehydrogenase and dehydratase activities, involved in the major pathways for threonine degradation in mitochondria and cytosol, respectively, were markedly decreased in rats with liver injury with a resulting increase in hepatic threonine concentration. Moreover, the threonine aldolase activity, which splits threonine into glycine and acetaldehyde, remained unaffected or even slightly increased. Liver injury was also associated with impaired mitochondrial functions, including a 10 to 23% decrease in acetaldehyde oxidation (depending upon the severity of the lesions). As a consequence, administration of ethanol (an exogenous source of acetaldehyde) resulted in striking elevations in the levels of acetaldehyde in carbon tetrachloride-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗
PubMed1987

Characteristics of acetaldehyde metabolism in isolated dog, rat and guinea-pig kidney tubules.

The metabolism of acetaldehyde was studied in isolated dog, rat and guinea-pig kidney-cortex tubules. In contrast with previous observations of Cederbaum and Rubin in rat kidney mitochondria (Archs Biochem. Biophys. 179, 46-66 1977) acetaldehyde was found to be metabolized by the tubules at high rates and in a dose-dependent manner at concentrations up to 5-10 mM. At high acetaldehyde concentrations (1-10 mM) acetaldehyde removal was accompanied by a high rate of acetate accumulation which explained most of the acetaldehyde metabolized in dog and guinea-pig but not in rat kidney tubules. These species differences in acetaldehyde metabolism can be explained by the differences in activities of aldehyde dehydrogenase (EC 1.2.1.3) and acetyl-CoA synthetase (EC6.2.1.1), the enzymes involved in renal acetaldehyde metabolism which were measured in the renal cortex of the three species. The acetaldehyde carbon removed and not accounted for by acetate accumulation was completely oxidized to CO2 as demonstrated by the measurement of [U-14C]-acetaldehyde conversion into 14CO2. At "physiological" acetaldehyde concentrations (0.1 and 0.2 mM) acetaldehyde utilization was also concentration-dependent but no acetate accumulation was observed.

Acetaldehyde↗
PubMedDate not supplied

Breath acetaldehyde following ethanol consumption.

Five pairs of volunteers were studied to determine the effect of drinking ethanol on breath acetaldehyde levels. On a given study day, samples of breath were obtained for measurement of acetaldehyde and ethanol from both participants at t = -1 h, t = -0.5 h, and at t = 0 to obtain baseline values. The drinkers were then given ethanol (0.3 g/kg body weight), and the controls given an equal volume of tap water. Breath samples were then taken at 0.5, 1, 1.5, 2 h, and hourly until t = 6 h. The last sample taken was at t = 23.5 h. Acetaldehyde levels in breath were quantified with a fluorigenic high-performance liquid chromatographic assay. Blood ethanol was approximated using a breath analyzer. Acetaldehyde in breath rose 50-fold at the 0.5-h, time point and returned to levels not significantly different from baseline values by 3-4 h. The mean peak blood ethanol values reached 0.055%. The t 1/2 elimination for ethanol was 1.6 h, and that for acetaldehyde was 2.25 h. Elimination of both acetaldehyde and ethanol in breath were initially 0 order. A significant correlation (r = 0.74) was found between baseline breath acetaldehyde levels and peak acetaldehyde levels. We conclude that acetaldehyde resulting from ethanol intake rapidly partitions into breath. The correlation of baseline breath acetaldehyde values with peak values found after an ethanol challenge indicate that measurement of breath acetaldehyde may be useful in the identification of individual differences in ethanol metabolism.

Acetaldehyde↗
PubMedDate not supplied

The formation of stable acetaldehyde-hemoglobin adducts in a red blood cell model.

The formation of stable hemoglobin adducts was examined (in the absence of an added reducing agent) in metabolizing red blood cells (RBCs) exposed to micromolar concentrations of acetaldehyde for up to 48 hours in vitro. The rapid disappearance of acetaldehyde due to oxidation by RBC aldehyde dehydrogenase was prevented by pretreating the cells with the inhibitor cyanamide. The RBCs remained viable for 48 hours (37 degrees C) as determined by cell hemolysis and glycolytic activity. [14C]acetaldehyde-modified hemoglobin was assessed in untreated and in cyanamide-pretreated cells. In untreated cells, after 3 hours of exposure to 50 and 200 nmol/ml of [14C]acetaldehyde, the molar ratios of acetaldehyde to hemoglobin were 0.00069 and 0.0038, respectively; [14C]acetaldehyde concentrations decreased to less than 4% of the initial levels within 3 hours. In cyanamide-pretreated RBCs, the molar ratios of acetaldehyde bound to hemoglobin ranged from 0.0013 after 3 hours of exposure to 20 nmol/ml [14C]acetaldehyde up to 0.039 after 48 hours of exposure to 200 nmol/ml [14C]acetaldehyde. Following tryptic digestion of [14C]acetaldehyde-hemoglobin and separation of peptides by high-performance liquid chromatography, significant incorporation of [14C]acetaldehyde was observed in nine peptides. Modifications of the labeled peptides remain to be characterized.

Acetaldehyde↗
PubMed2005

Pro- and anti-apoptotic roles of c-Jun N-terminal kinase (JNK) in ethanol and acetaldehyde exposed rat hepatocytes.

We have examined the significance of the activation of c-Jun N-terminal kinase (JNK) and p42/44 mitogen-activated protein kinase (MAPK) by ethanol and acetaldehyde in rat hepatocyte apoptosis. Acetaldehyde induced rapid and transient (15 min) activation of p42/44 MAPK followed by activation of JNK, which remained above control up to 1 h. Ethanol activated JNK for up to 4 h. Both ethanol and acetaldehyde caused apoptosis as determined by DNA fragmentation, caspase-3 activation and 2'[4-ethoxyphenyl]-5-[4-methyl-piperazinyl]-2,5'-bi-1H-benzimidazole (Hoechst 33342) staining. Ethanol-induced apoptosis was blocked by JNK inhibitor 1,9-pyrazoloanthrone (SP600125), indicating that JNK activation is pro-apoptotic. In contrast, acetaldehyde-induced apoptosis was not suppressed by this inhibitor. In fact, SP600125 potentiated acetaldehyde-induced apoptosis, suggesting that JNK activation is anti-apoptotic. Inhibition of p42/44 MAPK by MAPK kinase (MKK1) inhibitor, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126), potentiated apoptosis by acetaldehyde or ethanol, suggesting anti-apoptotic role of p42/44 MAPK. The activation of JNK by ethanol or acetaldehyde was insensitive to the genistein (tyrosine kinase inhibitor), GF109203X (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide, protein kinase C [PKC] inhibitor) and N-acetylcysteine (N-AC) (antioxidant), whereas p42/44 MAPK activation by acetaldehyde was inhibited by genistein and GF109203X. Furthermore, p42/44 MAPK activation is not necessary for the JNK activation. In summary, transient activation of JNK by acetaldehyde is anti-apoptotic, whereas sustained activation of JNK by ethanol is pro-apoptotic. The activation of p42/44 MAPK appears to be anti-apoptotic for both ethanol and acetaldehyde. Thus, JNK activation by ethanol and acetaldehyde can be both pro- and anti-apoptotic in hepatocytes.

Acetaldehyde↗