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PubMed1976

Characteristics of acetaldehyde oxidation in rat liver mitochondria.

Rat liver mitochondria oxidized acetaldehyde (180 muM) at the rate of approximately 12 nmol/min/mg of protein at 37 degrees. This was stimulated by 88% with the addition of ADP. The ADP/O ratio (2.6) was similar to that with glutamate as substrate. 2,4-Dinitrophenol and phenazine methosulfate also stimulated the rate of acetaldehyde oxidation in the mitochondria. By contrast, acetaldehyde metabolism was virtually abolished by rotenone and antimycin A. These results indicate that acetaldehyde oxidation is linked to the mitochondrial respiratory chain and coupled with mitochondrial oxidative phosphorylation. Indeed, little acetaldehyde was metabolized when mitochondrial membranes were disrupted by sodium deoxycholate. In the disrupted mitochondria, however, acetaldehyde oxidation was fully recovered by addition of NAD+, suggesting that the ability of mitochondria to supply NAD+ controls the rate of acetaldehyde oxidation in intact mitochondria. The stimulatory effect of ADP on mitochondrial acetaldehyde oxidation was diminished by increasing the acetaldehyde concentration. Concomitantly, the ADP/O ratio decreased, suggesting an inhibitory effect of high concentrations of acetaldehyde on mitochondrial respiration. Chronic feeding of ethanol significantly reduced the capacity of intact liver mitochondria to oxidize acetaldehyde. This was associated with a significant reduction of the mitochondrial respiration. By contrast, the activity of aldehyde dehydrogenase in disrupted mitochondria remained unchanged.

Acetaldehyde↗
PubMed1998

Acetaldehyde-induced increase in paracellular permeability in Caco-2 cell monolayer.

Evidence indicates that endotoxin-mediated liver injury plays an important role in the pathogenesis of alcoholic liver disease. Elevated plasma endotoxin level in alcoholics is suggested to be caused by enteric bacterial overgrowth and/or increased intestinal permeability to endotoxin. In this study, the effect of ethanol and acetaldehyde on the paracellular permeability was evaluated in Caco-2 cell monolayers. Ethanol was administered into the incubation medium, whereas acetaldehyde was administered by exposing cell monolayers to vapor phase acetaldehyde, or by direct administration of an acetaldehyde generating system (AGS), ethanol + NAD+ + alcohol dehydrogenase. Paracellular permeability was assessed by measuring transepithelial electrical resistance (TER), sodium chloride dilution potential, and unidirectional flux of D-[2-(3)H]mannitol. Administration of ethanol up to 900 mM produced no significant effect on paracellular permeability. Vapor phase acetaldehyde, generated from 5 to 167 mM acetaldehyde solutions in neighboring wells, resulted in a time- and dose-dependent increase in acetaldehyde concentration (99 to 760 microM) in the buffer bathing cell monolayer. Acetaldehyde induced a reduction of TER and dilution potential, and an elevation of mannitol flux in a time and concentration-related manner, without affecting the ability of cells to exclude trypan blue. Removal of acetaldehyde after 1, 2, or 4 hr treatment and subsequent incubation in the absence of acetaldehyde resulted in a time-dependent reversal of TER to baseline values. Administration of AGS also reduced TER and dilution potential, associated with an increase in mannitol flux. This effect of AGS was prevented by 4-methylpyrazole, an alcohol dehydrogenase inhibitor. These results show that acetaldehyde, but not ethanol, reversibly increases the paracellular permeability of Caco-2 cell monolayer.

Acetaldehyde↗
PubMed2005

Microcalorimetric and infrared studies of ethanol and acetaldehyde adsorption to investigate the ethanol steam reforming on supported cobalt catalysts.

Microcalorimetric and infrared studies of ethanol and acetaldehyde adsorption were carried out on fresh and deactivated ZnO-supported cobalt catalysts (Co/ZnO and Co/ZnO(d), respectively) as well as on ZnO support alone. The results were used to analyze the catalytic behavior of these materials for ethanol and acetaldehyde steam-reforming reactions. The Co/ZnO(d) sample contained extensive carbon deposition as shown by Raman spectroscopy and transmission electron microscopy. On fresh Co/ZnO, the adsorption energetics of ethanol and acetaldehyde (an intermediate in the ethanol reforming reaction) were similar. Under steam-reforming conditions at low conversion values of ethanol, acetaldehyde was selectively yielded. The presence of surface acetate species was shown from IR spectra following acetaldehyde adsorption. Besides that, the Co/ZnO catalyst was active and showed a high selectivity toward the reforming products, H2 and CO2, when the steam reforming of acetaldehyde was carried out at low conversion values. In contrast, on the deactivated sample, the strongest adsorption sites of ethanol have disappeared, and acetaldehyde was adsorbed with higher energy with respect to ethanol, resulting in the blockage of the active sites; a poorer catalytic performance in both ethanol and acetaldehyde steam-reforming reactions is observed. The presence of acetate species after adsorption of acetaldehyde on Co/ZnO(d) was not shown. The polymerization of acetaldehyde over Co/ZnO(d) was related to the decomposition of acetaldehyde under reforming conditions to give CO and CH4.

Journal Article↗
PubMed1987

Three different proteins exhibiting NAD-dependent acetaldehyde dehydrogenase activity from Alcaligenes eutrophus.

The existence of three different proteins exhibiting NAD-dependent acetaldehyde dehydrogenase activity was confirmed in Alicaligenes eutrophus. The fermentative alcohol dehydrogenase, which also exhibits acetaldehyde dehydrogenase activity, is one of these proteins. The other two proteins were purified from A. eutrophus N9A mutant AS4 grown on ethanol applying chromatography on DEAE-Sephacel and triazine-dye affinity media. Acetaldehyde dehydrogenase II, which amounts to about 14% of the total soluble protein in cells grown on ethanol, was purified to homogeneity. The relative molecular masses of the native enzyme and of the subunits were 195,000 or 56,000, respectively. This enzyme exhibits a high affinity for acetaldehyde (Km = 4 microM). Acetaldehyde dehydrogenase I amounts only to less than 1% of the total soluble protein. The relative molecular masses of the native enzyme and of the subunits were 185,000 and 52,000, respectively. This enzyme exhibits a low affinity for acetaldehyde (Km = 2.6 mM). Antibodies raised against acetaldehyde dehydrogenase II did not react with acetaldehyde dehydrogenase I. Two different strains, A. eutrophus N9A mutant AS1, which represents a different mutant type and can utilize both ethanol or 2,3-butanediol, and the type strain of A. eutrophus (TF93), which can utilize ethanol, form two acetaldehyde dehydrogenases during growth on ethanol, too. As in AS4, one of these enzymes from each strain amounted to a substantial portion of the total soluble protein in the cells. These major acetaldehyde dehydrogenases were purified from both strains; they resemble acetaldehyde dehydrogenase II isolated from AS4 in all relevant properties. Antibodies against the enzyme isolated from AS4 gave identical cross-reactions with the enzymes isolated from AS1 and TF93.

Alcaligenes↗
PubMed1990

Formation of the 37-kD protein-acetaldehyde adduct in primary cultured rat hepatocytes exposed to alcohol.

We have previously reported that a 37-kD liver protein formed an adduct with acetaldehyde in vivo when rats were fed alcohol chronically. To understand the mechanism of the formation of this protein-acetaldehyde adduct, rat hepatocytes in primary culture were treated with ethanol in vitro for several days. When cultured in hormone-enriched and trace metal-enriched Waymouth's medium, alcohol dehydrogenase activities in hepatocytes decreased only about 30% during 6 days of culture. At the end of the specified time, protein extracts of hepatocytes were immunotransblotted with rabbit immunoglobulin G that recognized acetaldehyde adduct as an epitope. The 37-kD protein-acetaldehyde adduct band could be detected within 3 days in cells that had been treated with alcohol at a steady-state concentration as low as 5 mmol/L. Although the maximal intensity was obtained at approximately 10 to 40 mmol/L ethanol, addition of cyanamide (an inhibitor of aldehyde dehydrogenase) further increased the intensity of this protein-acetaldehyde adduct band by more than twofold. A good correlation existed between acetaldehyde concentration in the medium and the intensity of the 37-kD protein-acetaldehyde adduct band. Formation of the 37-kD liver protein-acetaldehyde adduct is thus dependent on acetaldehyde, and the 37-kD protein is apparently unusually susceptible to chemical modification by acetaldehyde.

Acetaldehyde↗
PubMed1995

Inhibition of gastric cell proliferation by acetaldehyde.

Helicobacter pylori possesses alcohol dehydrogenase activity and is capable of producing acetaldehyde from ethanol in vitro. Acetaldehyde is a toxic and reactive compound and has been shown to inhibit the proliferation of many different cell lines in vitro. To study the effects of acetaldehyde on the proliferation of gastric epithelial cells in vivo, we employed an immunohistochemical method after labelling proliferating cells with 5'-bromo-2'-deoxyuridine in rats receiving acetaldehyde intragastrically. Chronic (16 weeks) exposure of gastric mucosa to acetaldehyde given to rats in their drinking water in concentrations of 10 or 20 mM resulted in significant (P < 0.05) inhibition of gastric epithelial cell proliferation, expressed as 332 +/- 36, 348 +/- 8, and 695 +/- 15 proliferating cells per ten high-power (x 400) fields in the groups drinking 10 mM acetaldehyde, 20 mM acetaldehyde, and in controls respectively. In an acute study, significant inhibition of proliferation was observed after as few as 4 days of exposure to acetaldehyde, but only when a higher dose (50 mM) of acetaldehyde was given (438 +/- 44 versus 615 +/- 19 in controls, P < 0.05). The inhibition of gastric cell renewal by acetaldehyde may play a role in the pathogenesis of ethanol- and/or H. pylori-associated gastric diseases by inhibiting normal gastric mucosal protection and repair.

Acetaldehyde↗
PubMed1991

Ethanol-induced CTA mediated by acetaldehyde through central catecholamine activity.

The possible involvement of catecholamines (CA) in the mediation of acetaldehyde's conditioned taste aversion (CTA) was examined by testing the effects of alpha-methyl-para-tyrosine (AMPT, a tyrosine hydroxylase inhibitor) on the CTAs produced by acetaldehyde. AMPT blocked the acquisition of the CTA normally produced by a low dose of acetaldehyde (0.2 g/kg), but had no significant effect on CTA produced by a high dose of acetaldehyde (0.3 g/kg). In a second study, acetaldehyde's role in the CTA produced by ethanol was investigated using the pre-exposure conditioned taste aversion paradigm. Pre-exposure to acetaldehyde (both doses) blocked the ethanol CTAs but when pre-exposure with acetaldehyde was coupled with AMPT, only the larger dose of acetaldehyde blocked the ethanol aversion. These results suggest that while the CTA to the low dose of acetaldehyde may be primarily central and catecholamine-mediated, the mechanism underlying the high dose CTA is probably peripheral and emetic in nature. These findings support the conclusion that acetaldehyde may be mediating many of the actions of ethanol.

Acetaldehyde↗
PubMed1984

Effect of acetaldehyde and cyanamide on the metabolism of formaldehyde by hepatocytes, mitochondria, and soluble supernatant from rat liver.

Formaldehyde can be metabolized primarily by two different pathways, one involving oxidation by the low-Km mitochondrial aldehyde dehydrogenase, the other involving a specific, glutathione-dependent, formaldehyde dehydrogenase. To estimate the roles played by each enzyme in formaldehyde metabolism by rat hepatocytes, experiments with acetaldehyde and cyanamide, a potent inhibitor of the low-Km aldehyde dehydrogenase were carried out. The glutathione-dependent oxidation of formaldehyde by 100,000g rat liver supernatant fractions was not affected by either acetaldehyde or by cyanamide. By contrast, the uptake of formaldehyde by intact mitochondria was inhibited 75 to 90% by cyanamide. Acetaldehyde inhibited the uptake of formaldehyde by mitochondria in a competitive fashion. Formaldehyde was a weak inhibitor of the oxidation of acetaldehyde by mitochondria, suggesting that, relative to formaldehyde, acetaldehyde was a preferred substrate. In isolated hepatocytes, cyanamide, which inhibited the oxidation of acetaldehyde by 75 to 90%, produced only 30 to 50% inhibition of formaldehyde uptake by cells as well as of the production of 14CO2 and of formate from [14C]formaldehyde. The extent of inhibition by cyanamide was the same as that produced by acetaldehyde (30-40%). In the presence of cyanamide, acetaldehyde was no longer inhibitory, suggesting that acetaldehyde and cyanamide may act at the same site(s) and inhibit the same formaldehyde-oxidizing enzyme system. These results suggest that, in rat hepatocytes, formaldehyde is oxidized by cyanamide- and acetaldehyde-sensitive (low-Km aldehyde dehydrogenase) and insensitive (formaldehyde dehydrogenase) reactions, and that both enzymes appear to contribute about equally toward the overall metabolism of formaldehyde.

Acetaldehyde↗
PubMed1984

Blood and liver acetaldehyde concentrations during ethanol oxidation in C57 and DBA mice.

Hepatic and blood acetaldehyde concentrations during ethanol oxidation were determined in C57 and DBA mice. Liver acetaldehyde was determined with the perchloric acid-thiourea method (no artefactual acetaldehyde formation). Levels ranging from 5 to 118 nmole/g were observed. At ethanol concentrations below 50-60 mumole/g, liver acetaldehyde concentrations were higher in DBA compared with C57 mice. A positive correlation was found between the ethanol and acetaldehyde concentration, when ethanol concentration was below 25 (DBA) or 70 mumole/g (C57). At higher ethanol concentrations the correlations tended to become negative. Artefactual acetaldehyde formation during the analytical procedures was obtained with the use of hemolysis, with or without thiourea, and semicarbazide methods for blood acetaldehyde determination. The magnitude of the artefactually formed acetaldehyde was of such order that no conclusions regarding the existence of true in vivo blood acetaldehyde concentrations could be drawn. Earlier reported mice blood acetaldehyde concentrations are suggested to be re-evaluated.

Acetaldehyde↗
PubMed1987

Effects of acetaldehyde on polymerization of microtubule proteins.

The in vitro effects of ethanol and acetaldehyde on polymerization of calf brain microtubular proteins (MTP) were examined. While ethanol up to 100 mM had no effect on the polymerization of MTP, acetaldehyde above 0.5 mM had an inhibitory effect. This effect was not dependent on the presence of microtubule-associated proteins (MAPs), since acetaldehyde had a similar effect on the polymerization of highly purified tubulin. Electron microscopy revealed that the number and the length of microtubules at equilibrium was reduced by the presence of acetaldehyde. Acetaldehyde raised the critical concentration for tubulin assembly and caused greater inhibition at lower tubulin concentrations. Acetaldehyde augmented the depolymerizing effects of Ca2+ on preassembled microtubules. In addition, acetaldehyde itself caused depolymerization of microtubules but only in the absence of MAPs. Long-term (19.5 h) incubation of MTP with acetaldehyde led to significant loss of polymerization ability which could not be reversed by removal of acetaldehyde. This loss of activity was apparently independent of the observed formation of reducible adducts between acetaldehyde and MTP.

Acetaldehyde↗
PubMed1983

Teratogenicity of acetaldehyde in vitro: relevance to the fetal alcohol syndrome.

Day 10 rat embryos grown in vitro showed significant retardation in growth and development when culture media contained acetaldehyde. A concentration-response range for acetaldehyde-induced embryotoxicity was defined, from no effect at 5 microM to complete lethality at 100 microM. The relative teratogenicity of ethanol and acetaldehyde, and the potential roles of these compounds in producing the Fetal Alcohol Syndrome are discussed. Despite intensive investigation into alcohol teratogenicity, the mechanism that produces the Fetal Alcohol Syndrome (FAS) remains unknown. Observed anomalies may result from direct embryonic exposure to ethanol or one of its metabolites, or from some indirect effect such as altered placental function or maternal nutritional status. Use of in vitro techniques allows study of direct embryonic exposures in the absence of indirect influences. Under such conditions, ethanol has been found to exert direct embryotoxicity (1). Rat embryos, grown as cultured explants and subjected to ethanol concentrations of 32.5 or 65 mM, were retarded in growth and development when compared to untreated controls. In this paper, we report direct embrytoxic effects of acetaldehyde, the primary metabolite of ethanol, at concentrations as low as 25 microM. Acetaldehyde teratogenicity has not been extensively studied. Veghelyi et al. (2) and Lambert, Papp and Nishiura (3) employed a combination of ethanol and disulfiram (an inhibitor of acetaldehyde-oxidizing enzymes). Teratogenic effects exceeded expectations based upon assumption of an additive interaction between these two compounds, and were attributed to elevated maternal blood acetaldehyde. O'Shea and Kauffman (4,5) and Dreosti et al. (6) administered acetaldehyde to pregnant animals by injection. Treatment resulted in retarded growth and development, decreased DNA synthesis, and increased frequencies of malformation and resorption. While these studies imply a role for acetaldehyde in alcohol-induced teratogenesis, indirect effects through altered maternal or placental factors cannot be eliminated. We present here the first concentration-response data for direct embryonic exposure to acetaldehyde.

Acetaldehyde↗
PubMedDate not supplied

Regulation of the formation of stable adducts between acetaldehyde and blood proteins.

Recent reports have described increased levels of a fast-moving hemoglobin (Hb) fraction in alcoholic patients and formation in vitro of stable adducts between acetaldehyde and Hb as well as between acetaldehyde and albumin. In the present study, we have found that factors other than acetaldehyde concentration can influence the rate of stable adduct formation. HbAo was purified and its 2,3-diPglycerate removed by dialysis. Under anaerobic condition and at 37 degrees, acetaldehyde (5 microM) reacted with deoxyHbAo to form 0.26 +/- 0.02 (+/- SEM) nmol of stable adduct/149 nmol Hb in 2 hr. By comparison, acetaldehyde reacted more slowly with oxyHbAo and carbonylHbAo; the rates were 0.21 +/- 0.01 (p less than 0.001) and 0.18 +/- nmol/149 nmol Hb/2 hr (p less than 0.001), respectively. Pyridoxal 5'-phosphate (50-500 microM), under anaerobic condition, inhibited by 36-56 percent the irreversible binding of acetaldehyde to deoxyHbAo. Ascorbic acid (2.5-10 mM) increased by 31-46 percent (p less than 0.001) the irreversible binding of acetaldehyde to human serum albumin and by 8-10 percent (p less than 0.05) the irreversible reaction of acetaldehyde with serum proteins. We conclude that the nonenzymatic binding of acetaldehyde to Hb, human serum albumin and serum proteins is influenced by factors other than acetaldehyde concentration. These factors include oxygen tension, pyridoxal 5'-phosphate and ascorbic acid. Among these factors, oxygen tension may be the most important in vivo.

Acetaldehyde↗
PubMed2006

Acetaldehyde does not inhibit glutathione peroxidase and glutathione reductase from mouse liver in vitro.

Acetaldehyde, the primary ethanol metabolite, has been implicated in the pathogenesis of alcoholic liver disease, but the mechanism involved is still under investigation. This study aims at the search for direct in vitro effects of different concentrations of acetaldehyde (30, 100 and 300microM) on the activities of glutathione reductase (GR), glutathione peroxidase (GPx) from liver supernatants, and the thiol-peroxidase activity of ebselen. They did not change after pre-incubation with acetaldehyde, which suggests that acetaldehyde does not have any direct effect. Nor were direct effects of acetaldehyde toward thiols, such as dithioerythritol and glutathione (GSH), observed either, even though GSH - measured as non-protein thiols from liver supernatants - were oxidized in the presence of acetaldehyde. In addition, acetaldehyde (up to 300microM) significantly oxidized GSH when incubated in the presence of commercially available gamma-glutamyltranspeptidase (GGT), but not in the presence of glutathione-S-transferase. The interaction between ebselen and GSH was also evaluated in an attempt to better understand the possible link between acetaldehyde and nucleophilic selenol groups. The formation and stability of ebselen intermediaries, produced in the chemical interaction between GSH and ebselen, were not affected by acetaldehyde either. Overall, the acetaldehyde oxidation of hepatic low-molecular thiols depends on mouse liver constituents and GGT is proposed as an important enzyme involved in this phenomenon. Thiol depletion, a phenomenon usually observed in the livers of alcoholic patients, can be related to GSH metabolism, and the involvement of GGT may reflect a molecular mechanism involved in thiol oxidation.

Acetaldehyde↗
PubMed2006

Attenuation of acetaldehyde-induced cell injury by overexpression of aldehyde dehydrogenase-2 (ALDH2) transgene in human cardiac myocytes: role of MAP kinase signaling.

Acetaldehyde, the major metabolite of ethanol, which is far more toxic and reactive than ethanol, may be responsible for alcohol-induced cardiac damage. This study was designed to examine the impact of facilitated acetaldehyde metabolism using transfection of human aldehyde dehydrogenase-2 (ALDH2) transgene on acetaldehyde- and ethanol-induced cell injury. Fetal human cardiac myocytes were transfected with ALDH2, the efficacy of which was verified by flow cytometry, Western blot and ALDH2 activity assays. Generation of reactive oxygen species (ROS) was detected using 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA). Apoptosis was evaluated by 4',6'-diamidino-2'-phenylindoladihydrochloride (DAPI) fluorescence microscopy, quantitative DNA fragmentation ELISA and caspase 3 activity. Acetaldehyde and ethanol elicited overt ROS generation and apoptosis in human cardiac myocytes following 24-48 h of incubation. Immunostaining revealed activation of the MAP kinase cascades ERK1/2, SAPK/JNK and p38 MAP kinase in acetaldehyde-treated myocytes. Interestingly, ALDH2 transgene significantly attenuated acetaldehyde-induced ROS generation, apoptosis and phosphorylation of ERK1/2 and SAPK/JNK. Time-dependent response (0-12 h) revealed ROS accumulation and activation of MAP kinases prior to acetaldehyde-induced apoptosis. In addition, acetaldehyde-induced ROS generation and apoptosis were antagonized by non-enzymatic antioxidants. Our results suggested that ALDH2 transgene overexpression may effectively alleviate acetaldehyde-elicited cell injury through an ERK1/2 and SPAK/JNK-dependent mechanism. Our data are consistent with the notion of acetaldehyde as a contributor to alcoholic cardiomyopathy and implicate the therapeutic potential of ALDH2 enzyme in alcoholic complications.

Acetaldehyde↗
PubMed2001

Conditioned stimulus preference after acetaldehyde but not ethanol injections.

Acetaldehyde, the first ethanol metabolite, has been suggested to mediate some of the behavioral effects of ethanol and particularly its reinforcing properties, although this later hypothesis remains extremely controversial. While several studies demonstrated the reinforcing effects of brain acetaldehyde, blood acetaldehyde accumulation is believed to be primarily aversive. In the present study, a conditioned reinforcement procedure has been used to investigate the reinforcing and/or aversive effects of intraperitoneal injections of both acetaldehyde and ethanol in Wistar rats. An olfactory stimulus was paired with daily injections of either ethanol (0, 0.25, 0.5, 1 and 2 g/kg) or acetaldehyde (0, 10, 20, 100 and 150 mg/kg). After eight conditioning sessions, all rats were tested for their stimulus preference or aversion. The results show that conditioning with small, 0.25 and 0.5 g/kg, ethanol doses induced neither preference nor aversion for the olfactory cue. In contrast, higher ethanol doses (1.0 and 2.0 g/kg) resulted in significant stimulus aversions. Acetaldehyde conditioning led to a biphasic stimulus preference, with a maximal preference around 20 mg/kg acetaldehyde. No evidence of aversive effects was found with increasing doses of acetaldehyde, even with concentrations close to the lethal limit. The present study clearly shows that systemic acetaldehyde injections induced significant stimulus preferences. This suggests that acetaldehyde may be, at least in part, responsible for the reinforcing effects of alcohol intake.

Acetaldehyde↗
PubMed2002

Supraphysiological acetaldehyde levels suppress growth in chicken embryos.

Although exposure to ethanol is known to cause growth inhibition in a developing embryo, the contributing effect of acetaldehyde on growth is not as well documented. In this study, we measured acetaldehyde-induced growth suppression in three different chicken strains: Peterson x Hubbard, HY x Hubbard, and W36 Ginther White Leghorn. The chicken embryo provides a useful model for studying fetal alcohol syndrome (FAS) and has been used extensively in our laboratory. The current study was undertaken to determine whether the chicken embryo could serve as a model for studying the effects of acetaldehyde on growth. Acetaldehyde caused a significant reduction in embryonic weights only at the higher acetaldehyde concentrations. Torso-to-head ratios were unchanged at every acetaldehyde dose for all strains, supporting the suggestion that acetaldehyde-induced growth suppression was generalized in all tissues, rather than being exhibited as a selective decrease of neuronal tissue. All strains experienced a significant decrease in viability only at higher acetaldehyde concentrations, but differences in viability were evident among the strains. These results support findings obtained from previous work done on ethanol-induced differences among chicken strains by supporting the suggestion that the strain of chicken is important when studying the effects of teratogens on growth and viability. More importantly, the supraphysiological concentrations of acetaldehyde necessary to induce growth suppression seem to indicate that the chicken embryo may not be a viable model of FAS for studying the direct effects of acetaldehyde on embryonic growth.

Acetaldehyde↗
PubMedDate not supplied

Effects on endogenous acetaldehyde production by disulfiram and ethanol feeding on rat pancreas.

Exogenous acetaldehyde infusion can induce pancreatitis-like injury of the pancreas in some isolated pancreas models, whereas in vivo such treatment has failed to induce pancreatitis. In vivo exogenous acetaldehyde may not be effective because it is rapidly metabolized. The aim of this study was to investigate whether endogenous acetaldehyde accumulates in the pancreas after ethanol feeding when acetaldehyde metabolism is blocked by disulfiram, and whether this treatment can induce pancreatitis-like injury in the rat. The liver was studied for comparison. In part I of the experiment, adult male Wistar rats were given water (n = 24), ethanol (n = 24), disulfiram (n = 24), and ethanol plus disulfiram for 1 week (n = 24) or 3 weeks (n = 24) and for 3 weeks with (n = 6) and without (n = 6) hypovolemia. In part II of the experiment, rats were given water (n = 6), ethanol (n = 6), and high-dose disulfiram (n = 6) and ethanol plus high-dose disulfiram (n = 6). Ethanol and acetaldehyde concentrations in blood, liver, and pancreas were measured. Animal behavior was monitored, and weight changes, plasma amylase activity, water content, and histomorphology of the pancreas and liver were studied without knowing the group. No increases in plasma amylase activity and no histomorphologic changes in the pancreas were observed under light or electron microscopy in part I of the experiment. In part II, treatment with ethanol induced acetaldehyde accumulation in the liver (33.6 +/- 2.6 micromol/L), but to a lesser degree in the blood (9.6 +/- micromol/L) and pancreas (5.0 +/-.2 micromol/L). Ethanol plus disulfiram induced marked accumulation of acetaldehyde in the liver (83.2 +/- 15.9 micromol/L), blood (280.0 +/- 47.4 micromol/L), and pancreas (43.6 +/- 4.7 micromol/L). When tissue acetaldehyde levels reached 30 to 40 micromol/L, we found a decrease in zymogen granules along with formation of small intracytoplasmic vacuolizations in the acinar cells and accumulation of lipid droplets in the hepatocytes, whereas physiologic signs of pancreatitis (hyperamylasemia, edema) or increases in liver enzymes did not develop. High levels of acetaldehyde accumulate in the liver and pancreas with the treatment described. Although this was accompanied by lipid degeneration of the hepatocytes and some subcellular changes in the acinar cells, physiologic signs of pancreatitis did not develop. Thus acetaldehyde accumulation alone, or in combination with hypovolemia, is not responsible for the induction of acute pancreatitis.

Acetaldehyde↗
PubMed2000

Identification of DNA adducts of acetaldehyde.

Acetaldehyde is a mutagen and carcinogen which occurs widely in the human environment, sometimes in considerable amounts, but little is known about its reactions with DNA. In this study, we identified three new types of stable acetaldehyde DNA adducts, including an interstrand cross-link. These were formed in addition to the previously characterized N(2)-ethylidenedeoxyguanosine. Acetaldehyde was allowed to react with calf thymus DNA or deoxyguanosine. The DNA was isolated and hydrolyzed enzymatically; in some cases, the DNA was first treated with NaBH(3)CN. Reaction mixtures were analyzed by HPLC, and adducts were isolated and characterized by UV, (1)H NMR, and MS. The major adduct was N(2)-ethylidenedeoxyguanosine (1), which was identified as N(2)-ethyldeoxyguanosine (7) after treatment of the DNA with NaBH(3)CN. The new acetaldehyde adducts were 3-(2-deoxyribos-1-yl)-5,6,7, 8-tetrahydro-8-hydroxy-6-methylpyrimido[1,2-a]purine-10(3H)one (9), 3-(2-deoxyribos-1-yl)-5,6,7,8-tetrahydro-8-(N(2)-deoxyguanosyl+ ++)- 6-methylpyrimido[1,2-a]purine-10(3H)one (12), and N(2)-(2, 6-dimethyl-1,3-dioxan-4-yl)deoxyguanosine (11). Adduct 9 has been previously identified in reactions of crotonaldehyde with DNA. However, the distribution of diastereomers was different in the acetaldehyde and crotonaldehyde reactions, indicating that the formation of 9 from acetaldehyde does not proceed through crotonaldehyde. Adduct 12 is an interstrand cross-link. Although previous evidence indicates the formation of cross-links in DNA reacted with acetaldehyde, this is the first reported structural characterization of such an adduct. This adduct is also found in crotonaldehyde-deoxyguanosine reactions, but in a diastereomeric ratio different than that observed here. A common intermediate, N(2)-(4-oxobut-2-yl)deoxyguanosine (6), is proposed to be involved in formation of adducts 9 and 12. Adduct 11 is produced ultimately from 3-hydroxybutanal, the major aldol condensation product of acetaldehyde. Levels of adducts 9, 11, and 12 were less than 10% of those of N(2)-ethylidenedeoxyguanosine (1) in reactions of acetaldehyde with DNA. As nucleosides, adducts 9, 11, and 12 were stable, whereas N(2)-ethylidenedeoxyguanosine (1) had a half-life of 5 min. These new stable adducts of acetaldehyde may be involved in determination of its mutagenic and carcinogenic properties.

Acetaldehyde↗