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PubMed1984

Determination of the proximate teratogen of the mouse fetal alcohol syndrome. 2. Pharmacokinetics of the placental transfer of ethanol and acetaldehyde.

CD-1 mice were treated ip on Day 10 of gestation with 4, 6, or 7 g/kg ethanol. Maternal and embryonic tissues were analyzed for ethanol and acetaldehyde levels by head-space gas chromatography 5 min to 24 hr after treatment. Dose-dependent ethanol concentrations were observed in maternal blood and liver. Ethanol rapidly crossed the placenta and appeared in the embryo 5 min after treatment. Acetaldehyde was detectable in maternal blood following all treatments and in maternal liver and embryos following treatment with 7 g/kg ethanol. Coadministration of 100 mg/kg 4-methylpyrazole, an alcohol dehydrogenase inhibitor, with 4 or 6 g/kg ethanol on Day 10 of gestation significantly reduced the rate of ethanol elimination in all tissues examined. This reduction was manifested as a prolongation in the half-life of ethanol detectable in maternal and embryonic tissues but not in an increase in maximum ethanol concentrations. Within 5 min of maternal ip treatment with 200 mg/kg acetaldehyde on Day 10 of gestation, acetaldehyde was detectable in the embryo. These data suggest that both ethanol and acetaldehyde are accessible to the embryo during a critical period of development.

Acetaldehyde↗
PubMed1992

Upper respiratory tract deposition of inspired acetaldehyde.

Inhalation exposure of rodents to high concentrations of acetaldehyde produces lesions in the upper respiratory tract (URT, all regions of the respiratory tract anterior to and including the larynx). Information on the inhalation dosimetric relationships for this vapor are needed for a comprehensive understanding of its inhalation toxicity. Toward this end, uptake of acetaldehyde was measured in the surgically isolated URT of the urethane-anesthetized male F344 rat under unidirectional (50, 100, 200, or 300 ml/min) and cyclic (100 ml/min) flow conditions at inspired concentrations of 1, 10, 100, or 1000 ppm. Under all flow conditions URT deposition efficiency was strongly dependent on inspired concentration. URT deposition efficiency (under cyclic flow) averaged 76, 48, 41, and 26% at 1, 10, 100, and 1000 ppm, respectively. Nasal acetaldehyde dehydrogenase activity averaged 1.2 micrograms/min. Absolute acetaldehyde deposition rates (micrograms/min) at 100 and 1000 ppm exceeded this activity by 5- to 100-fold, suggesting a possible mechanism for the reduced deposition efficiency at high concentrations. URT deposition under unidirectional flow was strongly dependent on the inspiratory flow rate. The effect of flow rate on deposition was reasonably predicted by the mass-transfer model of Aharonson et al. (J. Appl. Physiol. 37, 654-657, 1974). The uptake coefficients determined from the unidirectional flow studies were used to predict uptake under cyclic flow by integration of the model. The predicted cyclic deposition efficiencies differed from the observed efficiencies by 2.3 +/- 4.3% (mean +/- SEM), suggesting this model might provide a reasonable first approximation for acetaldehyde uptake under cyclic breathing conditions.

Acetaldehyde↗
PubMed1991

Increased frequency of acetaldehyde-induced sister-chromatid exchanges in human lymphocytes treated with an aldehyde dehydrogenase inhibitor.

Acetaldehyde, the first metabolite of ethanol oxidation, in concentrations ranging from 100 microM to 400 microM caused a dose-dependent linear increase in the frequency of sister-chromatid exchanges (SCE) in cultured human peripheral lymphocytes. The SCE frequency was on an average 2-fold higher when the cells were exposed to the acetaldehyde after 24 h incubation instead of at the time of mitogen stimulation (0 h). When acetaldehyde was added together with the potent aldehyde dehydrogenase inhibitor 1-aminocyclopropanol (0.1 mM), the SCE response was significantly (p less than 0.05) increased. The present results indicate that acetaldehyde is metabolized within human lymphocytes, and, moreover, that alcohol consumption during treatment with drugs that inactivate aldehyde dehydrogenase may cause a further increased incidence of acetaldehyde-induced SCE and concomitant lesions.

Acetaldehyde↗
PubMed1982

Modification of sickle hemoglobin by acetaldehyde and its effect on oxygenation, gelation and sickling.

Erythrocytes from sickle cell anemia patients and chromatographically purified Hb S0 were incubated with 0.25 to 120 mM acetaldehyde for 15 min to 6 h at different temperatures and pH. Several hemoglobin adducts stable to dialysis were separated by Biorex 70 chromatography and the proportions of the adducts formed were dependent on the period of incubation, acetaldehyde concentration, pH and temperature. Acetaldehyde treatment showed an increase in solubility, minimum gelling concentration and oxygen affinity and a decrease in sickling which showed a dependence on Hb S modification. With 0.25 to 1 mM acetaldehyde, significant inhibition of sickling was observed without any effect on the physical characteristics of the hemoglobin molecule. Acetaldehyde may act as a gelation inhibitor as well as a cell sickling inhibitor.

Acetaldehyde↗
PubMed1994

Collagen-acetaldehyde adducts in alcoholic and nonalcoholic liver diseases.

Alcoholic and, to a lesser extent, nonalcoholic patients with liver disease have serum antibodies to acetaldehyde-protein adducts produced in vitro. These antibodies presumably reflect the presence of adducts in the liver, but the protein that triggers this immune response has not been identified. To study this, we measured the reactivity of cytosolic proteins to rabbit IgG developed against a P-450 2E1-acetaldehyde adduct, isolated from alcohol-fed rats, that recognizes acetaldehyde-modified epitopes in proteins. Adducts were determined on Western blots by scanning densitometry of antibody-linked alkaline phosphatase activity in 4 normal livers and in needle biopsy specimens from subjects with liver disease, 17 alcoholic and 14 nonalcoholic. In all livers, except for a normal one, we found a reactive protein of at least 200 kD, similar to the collagen-acetaldehyde adduct we reported to be markedly increased in rats with experimentally induced cirrhosis. The immunostaining intensity in the alcoholic patients with liver disease was eightfold (p < 0.01) and that in nonalcoholic patients with liver disease was fourfold, greater (p < 0.02) than the weak staining in normal livers; it correlated with the degree of inflammation and serum AST or gamma-glutamyl transpeptidase activities. The adduct was reproduced on incubation of normal cytosolic proteins with 2.5 mmol/L acetaldehyde, whereas higher concentrations yielded many additional adducts; the adduct also reacted with IgG antibody to rat collagen type I and disappeared after digestion with collagenase, suggesting that the target protein is a form of collagen.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗
PubMed1988

Evaluation of the oral toxicity of acetaldehyde and formaldehyde in a 4-week drinking-water study in rats.

A subacute oral toxicity study of acetaldehyde and formaldehyde was carried out in rats. Groups of ten male and ten female 5-wk-old rats received one of the aldehydes in the drinking-water for a period of 4 wk, acetaldehyde being given at dose levels of 25, 125 and 675 mg/kg body weight/day and formaldehyde at dose levels of 5, 25 and 125 mg/kg body weight/day. A group of 20 males and 20 females served as controls and received unsupplemented drinking-water ad lib. An additional group of ten males and ten females was given unsupplemented drinking-water in an amount equal to the amount of liquid consumed by the group given the top dose of formaldehyde. Food and liquid intake were decreased in the groups on the top dose of both acetaldehyde and formaldehyde. Hyperkeratosis of the forestomach, observed only in the top-dose rats, was the only adverse effect of acetaldehyde detected. Effects of formaldehyde, also observed only in the top-dose group, were yellow discoloration of the fur, decreased protein and albumin levels in the blood plasma, thickening of the limiting ridge and hyperkeratosis in the forestomach, and focal gastritis in the glandular stomach. It was concluded that in this study the no-observed-adverse-effect levels of acetaldehyde and formaldehyde were 125 and 25 mg/kg body weight/day, respectively.

Acetaldehyde↗
PubMed1990

Acetaldehyde metabolism by isolated hepatic mitochondria from rats consuming different amounts of ethanol.

We have previously reported that in rats, ethanol intake as low as 4 g/kg per day induced mitochondrial alterations, detected by a decrease in mitochondrial O2 uptake supported by substrates entering at the three sites of coupled phosphorylation. Since it has been reported that acetaldehyde oxidation occurs mainly inside the mitochondria, linked to the respiration chain, the effect of daily previous administration of low doses of ethanol during a month, on the acetaldehyde oxidation rate by intact rat liver mitochondria was studied. Determination of acetaldehyde oxidation rate and O2 uptake accompanying acetaldehyde removal by liver mitochondria indicates that the mean value of these parameters studied in rats consuming low amount of ethanol (0.5-3.0 g/kg per day) was significantly higher than that of controls drinking only water (P less than 0.001, in state 3, and P less than 0.05, in state 4). This enhancing effect of ethanol cannot be ascribed to an uncoupling of oxidative phosphorylation and also not to a change in aldehyde dehydrogenase activity which was measured in disrupted mitochondria. On the other hand, high ethanol consumption (4-7 g/kg per day), which alters mitochondrial function, did not decrease mitochondrial acetaldehyde oxidation, as compared to rats drinking water only. This result differs from the decrease induced by higher levels of previous ethanol intake (12-14 g/kg per day) as reported by several authors, showing that possibly this effect is dose dependent.

Acetaldehyde↗
PubMed1985

Acetaldehyde and morphine interaction in the preexposure conditioned taste aversion paradigm in the rat.

The interaction between acetaldehyde, the primary metabolite of ethanol, and morphine was examined in the preexposure conditioned taste aversion (CTA) paradigm. Rats that were preexposed to acetaldehyde did not display a CTA to morphine. While acetaldehyde at the dose tested did not induce a strong CTA, morphine preexposure, however, reversed the decrease in saccharin associated with acetaldehyde injection thus reflecting a symmetrical interaction between acetaldehyde and morphine. Implications for a mechanism of ethanol-opiates interaction are discussed.

Acetaldehyde↗
PubMed1987

The reaction of acetaldehyde with brain microtubular proteins: formation of stable adducts and inhibition of polymerization.

Stable adducts were formed by treatment of bovine brain microtubular proteins (MTP) with acetaldehyde, followed by gel filtration to remove excess acetaldehyde. The extent of stable adduct formation was determined using [14C]acetaldehyde and was correlated with acetaldehyde concentration and reaction time. Significant inhibition of MTP polymerization was observed at adduct concentrations of 0.6 mol acetaldehyde/mol tubulin dimer. The data suggest that repeated exposure of MTP to low concentrations of acetaldehyde, as would occur in the brain and other tissues of alcoholics, may inhibit MTP polymerization with neurological consequences.

Acetaldehyde↗
PubMed1987

Effect of chronic acetaldehyde intoxication on ethanol tolerance and membrane fatty acids.

Recent studies have suggested that acetaldehyde participates directly in the pathogenesis of alcoholism. Its action has been attributed mainly to its physico-chemical properties. Results of direct intoxication of laboratory animals with acetaldehyde have been reported, but only for short periods of exposure and at high doses. These are probably not representative of the conditions found during alcohol intoxication. The pulmonary route of administration described here enables long term intoxication with acetaldehyde, at levels corresponding to values measured during chronic ethanol intoxication. Chronic administration of acetaldehyde during 3 weeks induced a metabolic tolerance to ethanol as tested by the sleeping time after a challenge dose of ethanol; behavioural tolerance (measured by blood alcohol levels on waking) was not observed. At the end of the intoxication, phospholipid fatty acids of erythrocyte and synaptosome membranes were also analysed. Small changes in levels of the shorter fatty acids were observed in the phosphatidyl-choline fraction. By comparison with the effects of ethanol on the same membrane preparations, only a small part of this effect can be attributed to acetaldehyde. The first metabolite of ethanol has, however, a sure effect on the pattern of fatty acid phospholipids.

Acetaldehyde↗
PubMed1981

Acetaldehyde penetrates the blood-liquor barrier of goats.

Goats received ethanol or acetaldehyde via carotid arterial infusions. Cerebrospinal fluid (CSF) was sampled for a lateral cerebral ventricle and blood from a jugular vein. Ethanol infusions produced only negligible levels of acetaldehyde in blood and CSF, but acetaldehyde infusions resulted in high levels. In contrast to ethanol, acetaldehyde was rapidly eliminated from both blood and CSF after discontinuing the infusion. The results indicate that even small amounts of acetaldehyde easily penetrate the blood-liquor barrier of goats.

Acetaldehyde↗
PubMed1982

Urinary sulfur containing metabolites after administration of ethanol, acetaldehyde and formaldehyde to rats.

Acetaldehyde and formaldehyde react in vitro with cysteine to form a product, probably a thiazolidine derivative, which eluted as a single peak in cation exchange chromatography. The reactivity of formaldehyde was much higher than that of acetaldehyde. Rats were injected with single dose of 7.6, 6.2 and 2.5 mmol, respectively of ethanol, acetaldehyde and formaldehyde, and urine was analysed for alkali-hydrolysable thiol groups. Acetaldehyde caused a significant increase in urinary alkali-hydrolysable thiols. Ethanol and acetaldehyde treatment stimulated the ability of the urine to catalyse the iodine-azide reaction suggesting the presence of an excess of compounds containing C-S-atoms.

Acetaldehyde↗
PubMed1987

Hepatotoxicity of acetaldehyde in rats.

The ability of acetaldehyde to initiate hepatotoxicity as evidenced by enzyme leakage, hepatic fat accumulation and histological alterations was studied in rats. Neither oral nor intraperitoneal treatment with acetaldehyde had any hepatotoxic effect, even following aldehyde dehydrogenase inhibition by disulfiram. This is probably due to the inability of exogenously added acetaldehyde to penetrate liver cell membranes. In contrast, acetaldehyde derived metabolically from ethanol was capable of inducing moderate hepatotoxicity when it accumulated upon pretreatment with disulfiram. Acetaldehyde may thus be partly responsible for alcohol-induced liver damage.

Acetaldehyde↗
PubMedDate not supplied

A multi-dimensional examination of the positive reinforcing properties of acetaldehyde.

The suggestion that acetaldehyde may be endowed with positive reinforcing properties and may in fact mediate some of the psychopharmacological actions of ethanol has been examined by us and other investigators using a variety of paradigms. We first reported that non-dependent animals would self-administer acetaldehyde through an intra-cerebroventricular route. In addition, we have demonstrated that central infusion induced a conditioned place preference. We have also shown that an animal's propensity to self-administer acetaldehyde directly into the brain was related to its subsequent voluntary intake of ethanol. Lastly, we have reported that inhibition of acetaldehyde metabolism resulted in an enhancement of alcohol-induced euphoria in man. The data collected to date from four different paradigms strongly support the notion that acetaldehyde is endowed with positive reinforcing properties which may play a critical role in the mediation of ethanol euphoria.

Acetaldehyde↗
PubMedDate not supplied

Estimation of blood acetaldehyde during ethanol metabolism: a sensitive HPLC/fluorescence microassay with negligible artifactual interference.

A novel high performance liquid chromatographic (HPLC) procedure has been developed for the quantitation of acetaldehyde in 50 microliter samples of primate whole blood during ethanol metabolism. This microassay has a minimum detectable concentration of about 0.1 microM, displays an intra-assay precision under 10%, and is linear over a reasonable concentration range. Of importance is that negligible acetaldehyde is generated artifactually from ethanol during blood analysis. The assay is based on the reaction of acetaldehyde with 1,3-cyclohexanedione and ammonium ion to form a water-soluble fluorogenic adduct, which is separated by reversed phase HPLC and quantitated fluorometrically. Propionaldehyde, added as an internal standard, forms an analogous separable adduct. Blood acetaldehyde concentrations in Rhesus monkeys were between 1-2 microM 150 min after acute administration of ethanol (1.5 g/kg). Traces of endogenous components which are chromatographically identical with cyclohexanedione adducts of acetaldehyde and formaldehyde also were apparent in blood from monkeys and humans not given ethanol.

Acetaldehyde↗
PubMedDate not supplied

Ethanol intake: effect on liver and brain mitochondrial function and acetaldehyde oxidation.

The effect of a chronic ethanol consumption by forcing rats to drink a 20% v/v ethanol solution as sole drinking fluid, for 3 months, was evaluated on: liver and brain mitochondrial function, the capacity of isolated mitochondria to oxidize acetaldehyde, as well as on the low Km mitochondrial AlDH activity, in rats. The O2 uptake by liver and brain mitochondria in the presence of glutamate + malate, succinate or ascorbate + TMPD, was measured polarographically with a Clark electrode. Acetaldehyde oxidation was measured by the disappearance rate in presence of the intact or disrupted mitochondria (AlDH activity) by gas chromatography. Results indicate that an ethanol intake of 11 g/kg b.wt. per day produce a significant reduction of the liver mitochondrial respiration tested with all the substrates used, including acetaldehyde. In contrast, the activity of AlDH in disrupted mitochondria remained unchanged. These results are in accord with the idea that a progressive deterioration of liver mitochondrial function appears with the increase in amount of ethanol consumed, and that alterations of acetaldehyde oxidation by intact mitochondria can be detected before an alteration of the AlDH activity. Concerning the brain, this ethanol consumption regimen did not affect the brain mitochondrial respiration tested with glutamate + malate, succinate or ascorbate + TMPD, but it induces an increase in acetaldehyde oxidation rate by intact brain mitochondria. The imposed increase in the cerebral aldehyde oxidizing capacity could reflect a principal biochemical mechanism underlying neural adaptation to ethanol.

Acetaldehyde↗
PubMedDate not supplied

Acetaldehyde inhibits the anti-elastase activity of alpha 1-antitrypsin.

There are genetic and exogenous factors responsible for alpha 1-antitrypsin (alpha 1-AT) deficiency which may lead to cirrhosis of the liver and emphysema. The present study was initiated on a biochemical level in order to determine whether acetaldehyde, the major product of ethanol metabolism, is capable of influencing the physiological effect of alpha 1-AT upon elastase, an enzyme which is capable of inducing emphysema. The effects of acetaldehyde and ethanol upon elastase and alpha 1-AT were tested. Acetaldehyde at 0.3-M and 1.2-M concentrations inhibited the anti-elastase activity of alpha 1-AT. Acetaldehyde at 0.03-M and 0.07-M concentrations did not affect elastase activity and had a slight effect at 0.12-M levels. Equivalent amounts of ethanol were without influence upon elastase activity or alpha 1-AT function. These data provide biochemical support for the possibility that heterozygous males with lower than normal alpha 1-AT levels may be at much higher risk to develop liver disease, emphysema, and alpha 1-AT deficiency as a consequence of chronic exposure to ethanol and concomitant circulating acetaldehyde levels.

Acetaldehyde↗
PubMed2005

DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis.

Alcoholic beverage consumption is classified as a known human carcinogen, causally related to an increased risk of cancer of the upper gastrointestinal tract. The formation of acetaldehyde from ethanol metabolism seems to be the major mechanism underlying this effect. Acetaldehyde is carcinogenic in rodents and causes sister chromatid exchanges and chromosomal aberrations in human cells. The best-studied DNA adduct from acetaldehyde is N(2)-ethyl-2'-deoxyguanosine, which is increased in liver DNA obtained from ethanol-treated rodents and in white blood cells obtained from human alcohol abusers. However, the carcinogenic relevance of this adduct is unclear in view of the lack of evidence that it is mutagenic in mammalian cells. A different DNA adduct, 1,N(2)-propano-2'-deoxyguanosine (PdG), can also be formed from acetaldehyde in the presence of histones and other basic molecules. PdG has been shown to be responsible for the genotoxic and mutagenic effects of crotonaldehyde. The PdG adduct can exist in either of two forms: a ring-closed form or a ring-opened aldehyde form. Whereas the ring-closed form is mutagenic, the aldehyde form can participate in the formation of secondary lesions, including DNA-protein cross-links and DNA interstrand cross-links. The formation of these types of complex secondary DNA lesions resulting from PdG may explain many of the observed genotoxic effects of acetaldehyde described above. Repair of PdG and its associated adducts is complex, involving multiple pathways. Inherited variation in the genes encoding the proteins involved in the repair of PdG and its secondary adducts may contribute to susceptibility to alcoholic beverage-related carcinogenesis.

Acetaldehyde↗