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PubMed1985

Acetaldehyde-dependent oxidation of glutathione catalyzed by rat liver cytosol.

We have identified a novel reaction in which acetaldehyde promotes rat hepatic cytosolic catalysis of O2 consumption coupled with glutathione oxidation without apparent release of activated forms of O2. Acetaldehyde is not consumed in the reaction. The reaction (O2 consumption or oxidized glutathione production) is saturable with respect to varying glutathione (K'm congruent to 20-45 microM) but not at high acetaldehyde concentrations. However, activity in the range of acetaldehyde found in liver from alcohol metabolism (10-100 microM) appeared to be saturable (K'm congruent to 25-50 microM). Since neither acetaldehyde-dependent glutathione loss nor O2 consumption is detectable in guinea pig hepatic cytosol or hepatic cytosol from selenium-deficient rats, we propose that acetaldehyde interacts with glutathione peroxidase, converting the enzyme into a glutathione oxidase.

Acetaldehyde↗
PubMed1985

Irreversible inhibition by acetaldehyde of cholecystokinin-induced amylase secretion from isolated rat pancreatic acini.

Acetaldehyde inhibited both amylase secretion induced by maximal concentrations (300 pM) of cholecystokinin octapeptide and the binding of radioiodinated cholecystokinin to receptors on isolated rat pancreatic acini. This inhibition was concentration dependent (10 mM to 1 M for amylase secretion and 100 mM to 1 M for binding). However, a correlation between the two inhibitory effects could not be obtained. Furthermore, the inhibitory effects were not reversible. Acetaldehyde did not alter the basal amylase secretion between 6 and 45 mM concentrations. However, 60, 100 and 300 mM acetaldehyde significantly decreased basal amylase secretion; no significant change in amylase secretion was observed at 600 mM and 1 M. Higher concentrations of acetaldehyde produced a 2- to 10-fold increase in basal amylase secretion. 51Cr release from prelabeled acini revealed no significant cell membrane damage between 10 and 600 mM acetaldehyde. These data suggest that acetaldehyde inhibition of cholecystokinin-induced amylase secretion is intracellularly mediated.

Acetaldehyde↗
PubMed1985

Endogenous acetaldehyde in rats. Effects of exogenous ethanol, pyrazole, cyanamide and disulfiram.

Male Long-Evans rats consumed the alcohol and aldehyde dehydrogenase inhibitors pyrazole, cyanamide or disulfiram, for 6 days. No endogenous blood acetaldehyde could be detected in controls and pyrazole treated rats, endogenous blood concentrations up to 2-5 nmoles/ml were, however, measured in the cyanamide and disulfiram-treated animals. Other rats received daily ethanol gastric intubations in addition to the consumption of the inhibitors. Little or no acetaldehyde was detected in the controls and pyrazole treated animals during acute ethanol intoxication or on the subsequent days. High blood levels (200-500 nmoles/ml) were observed in the rats consuming cyanamide and disulfiram, and concentrations up to 10-12 nmoles/ml were still found on the following day after all the ethanol had been eliminated. This acetaldehyde and the endogenous acetaldehyde could only be observed with the hemolyzation method in which blood hemolyzates were directly heated prior to headspace GC analysis; none was detected if blood proteins were first precipitated and removed with perchloric acid. It is suggested that aldehyde dehydrogenase inhibitors elevate endogenous concentrations of bound acetaldehyde and that exogenous ethanol increases this form of acetaldehyde.

Acetaldehyde↗
PubMed1985

Effects of disulfiram on the oxidation of benzaldehyde and acetaldehyde in rat liver.

The in vitro oxidation of benzaldehyde and acetaldehyde was studied in liver samples from disulfiram-treated and control rats. With 25 microM substrate, both cytosol and mitochondria appeared to make a nearly equal contribution to the oxidation of benzaldehyde, whereas ca. 90% of acetaldehyde oxidation occurred in mitochondria. When the Km values for benzaldehyde with aldehyde dehydrogenase (ALDH) were determined, two Km values (3 and 120 microM) were obtained with mitochondria, but only a single Km value (25 microM) was obtained with the cytosolic fraction. The relatively high Km (2.9 mM) found with microsomes makes it unlikely that microsomes are important in the oxidation of benzaldehyde. In intact mitochondria, with 200 microM acetaldehyde or benzaldehyde the matrix space enzyme accounted for 77 and 62%, respectively, of the total ALDH activity. When the activity was determined in a mixture containing both substrates, the activity was found not to be additive, indicating that both substrates are oxidized by the same matrix space enzyme. With subcellular fractions, from livers of disulfiram-treated and control rats, a greater degree of inhibition of ALDH was obtained when acetaldehyde was a substrate compared to that with benzaldehyde in cytosol and mitochondria. Microsomal ALDH was not inhibited by disulfiram. In liver slices from rats given disulfiram, a statistically significant inhibition was found when either 25 or 250 microM acetaldehyde was used (46 and 33%). With benzaldehyde, a significant inhibition (24%) was observed only with the lower substrate concentration. Finding that both mitochondrial fractions and slices were less inhibited at the higher substrate concentration implies that the high Km enzyme is not inhibited. It can be concluded that, in rat, disulfiram inhibiting liver ALDH not only affects oxidation of acetaldehyde, but also that of benzaldehyde.

Acetaldehyde↗
PubMed1995

The influence of brain acetaldehyde on oxidative status, dopamine metabolism and visual discrimination task.

The toxic effect of acetaldehyde on brain oxidative capacity and dopamine metabolism has been investigated in rat brains after a single intraperitoneal injection of acetaldehyde (5 mmol/kg) and the results compared with those from chronically ethanol fed rats. Acetaldehyde was present in rat brain 120 hr after a single dose of acetaldehyde, confirming that it is able to cross the blood-brain barrier. Brain catalase increased significantly after acetaldehyde or chronic ethanol administration although there were no other significant changes in the total brain activity of superoxide dismutase, glutathione peroxidase or glutathione reductase. Dopamine turnover was increased in both experimental groups. The acute dose of acetaldehyde reduced the ability of the rats to relearn a computer visual discrimination task.

Acetaldehyde↗
PubMed1989

MPTP treatment combined with ethanol or acetaldehyde selectively destroys dopaminergic neurons in mouse substantia nigra.

We have previously reported that ethanol and acetaldehyde potentiate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice, enhancing dopamine (DA) depletion in the striatum. The present study was designed to determine whether such enhancement of neurotoxicity was specific for the nigro-striatal DA pathway. In 5-week-old mice acetaldehyde treatment did not enhance DA depletion seen 7 days after MPTP treatment. In 8-week-old animals, however, acetaldehyde or ethanol given with MPTP decreased striatal DA content to about 10% of controls, whereas the depletion was to 43% of controls when MPTP was given alone. In acetaldehyde or ethanol and MPTP-treated mice, changes in DA levels were observed only in the striatum. DA contents in the hypothalamus, olfactory bulb and frontal cortex were similar to that in controls. Contents of norepinephrine and serotonin in striatum, hypothalamus, olfactory bulb and cerebral cortex were not affected by any of the treatments. Three months after MPTP alone, striatal DA recovered to 74% of controls in 8-week-old mice, whereas no recovery occurred in acetaldehyde and MPTP-treated mice. Moreover, both tyrosine hydroxylase (TH) immunocytochemistry and Cresyl violet staining showed an extensive and selective cell loss in the pars compacta of the substantia nigra (SNc) of the mice treated with acetaldehyde or ethanol and MPTP, whereas MPTP alone caused only a limited cell degeneration.

Acetaldehyde↗
PubMed1990

Effects of acetaldehyde on contractile response to nerve stimulation in guinea-pig vas deferens.

Twitch contractions of the isolated guinea-pig vas deferens induced by sympathetic nerve stimulation were augmented by acetaldehyde (0.1-10 mM). With high concentrations (5-10 mM), acetaldehyde produced a biphasic response consisting of an initial brief depression and a subsequent potentiation of the contraction. The late effect was associated with repetitive contractions that were not prevented by tetrodotoxin. A low concentration of phentolamine (27 microM) increased and a high concentration (1.3 mM) suppressed the potentiating action of acetaldehyde. Acetaldehyde did not induce contractions in surgically sympathectomized vasa or vasa pretreated with reserpine. Acetaldehyde caused a dose-dependent increase in noradrenaline release into the bathing fluid. The study shows that acetaldehyde has a dual effect on sympathetic neuroeffector transmission, and that an increase in noradrenaline secretion appears to contribute to the late facilitatory effect in the isolated vas deferens.

Acetaldehyde↗
PubMed1990

Effects of acetaldehyde on electrical activity during neuroeffector transmission in guinea-pig vas deferens.

The effects of acetaldehyde on electrical activity during sympathetic neuroeffector transmission were studied in the guinea-pig vas deferens. Application of 1 mM acetaldehyde produced a slow depolarization of the smooth muscle membrane. The amplitudes of facilitated excitatory junction potentials (EJPs) evoked by nerve stimulation were slightly decreased. A higher concentration of acetaldehyde (5 mM) initially hyperpolarized and later depolarized the membrane. The decrease in EJP amplitudes was more pronounced during hyperpolarization. Acetaldehyde (5 mM) increased the frequency of the spontaneous EJPs and reduced their amplitudes, whereas action potentials in postganglionic nerves were unaffected. Acetaldehyde (1-5 mM) decreased the amplitudes of EJPs in vasa pretreated with reserpine but did not alter the resting membrane potentials. The decrease in the EJP amplitudes together with the hyperpolarization of the membrane could be responsible for the early inhibitory effect of acetaldehyde on neuroeffector transmission. The slow depolarization, which is presumably mediated by endogenous noradrenaline, may cause the late facilitatory effect.

Acetaldehyde↗
PubMed1985

Reversible acetaldehyde inhibition of A23187-stimulated amylase secretion from isolated rat pancreatic acini.

The Ca2+ ionophore, A23187, stimulated amylase secretion from isolated rat pancreatic acini in a dose-dependent manner with a maximal effect at 6 microM. Acetaldehyde, a metabolite of ethanol, caused a reduction in the magnitude of ionophore-stimulated secretion with no evidence of competitive inhibition. Furthermore, 6 microM ionophore-stimulated amylase secretion was dose-dependently inhibited by acetaldehyde. This inhibitory effect of acetaldehyde, however, was reversible on washing and reincubating acetaldehyde-treated acini. These results suggest that acetaldehyde reversibly inhibits intracellular components mediating stimulated secretion and this inhibition requires a continuous chemical interaction between acetaldehyde and intracellular component(s) regulating stimulated enzyme secretion.

Acetaldehyde↗
PubMed1994

Formation and stability of acetaldehyde-induced crosslinks between poly-lysine and poly-deoxyguanosine.

The amino acid residue and nucleoside specificity of acetaldehyde-induced DNA-protein crosslinks (DPXLs) were studied using a modified filter binding assay. A 40% inhibition of acetaldehyde-induced pUC13 plasmid DNA-calf thymus histone crosslink formation was achieved by addition of 50 mM lysine (free base), while arginine was unable to affect crosslink formation at concentrations to 150 mM. Polymers (5-mers) of lysine (poly-lys5) were able to substitute for histones in acetaldehyde-induced plasmid crosslink formation, being equally effective at equimolar concentrations. Homopolymers (6-mers) of deoxyguanosine (poly-dG6) (but not deoxyadenosine, deoxycytidine or thymidine) served as an efficient substrate for acetaldehyde-induced DPXL formation, using either calf thymus histones or poly-lys5 as the protein source. Acetaldehyde-induced crosslinks between poly-dG6 and poly-lys5 were formed rapidly, but were unstable at 37 degrees C (a half-life or 1.5-2 h). Stability of these crosslinks was unaffected by pH at a range of 5.5-9.0 at 37 degrees C for 2 h. Results presented here suggest that unstable complexes of deoxyguanosine and lysine constitute a major portion of the DPXLs formed by acetaldehyde in vitro.

Acetaldehyde↗
PubMed1983

Potentiation of ethanol toxicity by cyanamide in relation to acetaldehyde accumulation.

The possibility that acetaldehyde accumulation potentiates the acute toxicity of ethanol was studied by pretreating rats with cyanamide, an aldehyde dehydrogenase inhibitor. At 30 min after administration of ethanol (7 to 9 g/kg, po), the levels of acetaldehyde in femoral venous blood of cyanamide-treated rats were increased from 10 to 20 to 600 mumol/liter and at death the concentrations of acetaldehyde in heart blood and cerebrospinal fluid were still 7 to 9 and 4 to 9 times higher, respectively, than in rats given ethanol only. The cyanamide pretreatment (25 mg/kg) significantly increased the mortality of rats given 6.5 to 7.0 g/kg ethanol and decreased the LD50 of ethanol from 7.3 to 5.9 g/kg. Cyanamide increased the late mortality, possibly because of sustained acetaldehyde accumulation. Although administration of the alcohol dehydrogenase inhibitor, 4-methylpyrazole (4-MP, 10 mg/kg), prevented the accumulation of acetaldehyde, it only partly counteracted the effect of cyanamide on mortality. After coadministration of cyanamide and 4-MP, the LD50 of ethanol was 6.5 g/kg, and after 4-MP alone, 6.7 g/kg. 4-MP by itself seemed to increase the early mortality of rats to ethanol poisoning. The results suggest that the potentiating effect of cyanamide on ethanol toxicity can partly be explained by acetaldehyde accumulation and that 4-MP can be used to inhibit this accumulation providing its central depressant effect is taken into account.

Acetaldehyde↗
PubMed1985

Effect of tolbutamide and chlorpropamide on acetaldehyde metabolism in two inbred strains of mice.

The mechanisms by which chlorpropamide and tolbutamide disrupt acetaldehyde metabolism were studied in C57BL and DBA mice. Acute po administration of varying doses of tolbutamide or chlorpropamide 2.5 hr before a 3.0 g/kg ip dose of ethanol to C57BL and DBA mice resulted in significant elevations of blood acetaldehyde when measured 2.5 hr after ethanol dosing. Dose-response analysis revealed a significant (p less than .05) difference in ED50 values for the elevated blood acetaldehyde response to tolbutamide in DBA (60 mg/kg) and C57BL (100 mg/kg) mice. The ED50 value for potentiation by chlorpropamide of blood acetaldehyde concentration was similar (23 to 32 mg/kg) in both inbred strains. At higher doses of chlorpropamide, DBA mice displayed elevations of blood acetaldehyde nearly threefold greater than those measured in C57BL mice treated identically. Measurements of aldehyde dehydrogenase (ALDH) in hepatic subcellular fractions, obtained from both inbred strains treated with 100 mg/kg tolbutamide or chlorpropamide prior to a 3.0 g/kg dose of ethanol, revealed a 50 to 80% inhibition of the low-Km ALDH present in mitochondria. Chlorpropamide and tolbutamide did not inhibit ALDH in vitro, suggesting that metabolites of these hypoglycemic agents may be responsible for the genotypic-dependent alterations in in vivo acetaldehyde oxidation.

Acetaldehyde↗
PubMed1989

Cytoprotective value of lysine, penicillamine, and pyridoxal phosphate against the neurotoxicity of acetaldehyde.

Rats which received acetaldehyde by intraperitoneal injection on a single occasion sustained neural degeneration in the cerebral cortex detectable with both light and electron microscopy. The degeneration was more intense and included the hippocampus when acetaldehyde exposure was given on 5 consecutive days in the form of ethanol vapor inhalation and disulfiram injections. Pretreatment of animals with a combination 2.5 g lysine/kg plus 50 mg pyridoxyl phosphate/kg did not alter the degree of degeneration response to either a single injection of acetaldehyde or 5 days acetaldehyde treatment. Penicillamine injections (1.2 g/kg) did offer some (but not complete) cytoprotective value against the neurotoxicity of acetaldehyde. This cytoprotective action was effective at concentrations of acetaldehyde which are not distant from clinically observed concentrations.

Acetaldehyde↗
PubMed1980

A quantitative analysis of ethanol and acetaldehyde expired by inbred mouse strains.

Expired ethanol and acetaldehyde were measured after an oral injection of ethanol in C57BL/6J and DBA/2J mouse strains by a combination of several techniques in a sequence involving a method for trapping expired radioactive compounds, separation of compounds by gas chromatography, isolation of radioactive ethanol and acetaldehyde, and their quantitative analysis by liquid scintillation spectrophotometry. With the specific activities used in evaluation of the technique (0.1 Ci/mole, acetaldehyde; 1.1 Ci/mol, ethanol) the lower limit of sensitivity using 500 microliters from a 10 ml trap is 955 pmoles for acetaldehyde and 101 pmoles for ethanol. However, in the animal experiments, injected ethanol has a specific activity of 1.1 Ci/mol which would make the specific activity of expired metabolically formed acetaldehyde the same. This results in a lower limit of sensitivity for acetaldehyde of 80 pmoles. The two strains were monitored for 80 min following an oral injection of 3.8 g/Kg of (2-14C) ethanol. Comparing the two strains on the expiration of each compound the curves were identical.

Acetaldehyde↗
PubMed1983

Human blood acetaldehyde concentration during ethanol oxidation (update 1982).

A wide variety of levels of human blood acetaldehyde have been reported in the past. During the last few years, however, it has become increasingly evident that most, if not all, of the previously observed acetaldehyde concentrations during normal (i.e., no deficiency in, or inhibition of, aldehyde dehydrogenase activity) ethanol oxidation merely reflected artefactual acetaldehyde formed during the analytical procedures. The artefactual acetaldehyde formation, which occurs mainly during blood protein precipitation, is effectively minimized by the recently improved PCA method in which blood is immediately mixed with a perchloric acid-saline solution, and by the semicarbazide method in which blood is treated with a fresh isotonic semicarbazide solution before removal of the plasma. Nevertheless, a procedure involving control blood with ethanol added should be employed to control for any artefactual acetaldehyde still produced. Based on the improved analytical procedures, no detectable acetaldehyde was found in the venous blood of Caucasian subjects after acute ethanol intake.

Acetaldehyde↗
PubMed1983

Uptake and oxidation of acetaldehyde by intact human erythrocytes.

Human erythrocytes were examined for acetaldehyde-oxidizing capacity of intact cells, in comparison with its uptake under various conditions. The oxidation was found to be predominant over other possible acetaldehyde-metabolizing pathways, particularly with low concentrations of acetaldehyde. Further investigation using three media which differed in the initial pyruvate level showed an independence of acetaldehyde oxidation rate up to the high cellular lactate/pyruvate concentration ratio. The apparent non-oxidative acetaldehyde uptake obtained by subtraction of oxidation from the total uptake, was reduced when pretreating the erythrocytes with pyridoxal but not with pyridoxal 5'-phosphate. Though N-ethylmaleimide also inhibited the non-oxidative uptake, another sulfhydryl blocking reagent, p-chloromercuribenzoate was without effect. Thus, in addition to the oxidation, acetaldehyde may be involved in a reaction such as binding to the red cell components, as the minor metabolizing pathway in the erythrocytes.

Acetaldehyde↗
PubMedDate not supplied

Blood acetaldehyde response to ethanol ingestion during the reproductive cycle of the female rat.

Acetaldehyde could mediate a number of the toxic effects of alcohol both in females and their offspring. Thus, we assessed the blood acetaldehyde response to ethanol (3 g/kg) at various stages of the female reproductive cycle. Blood levels were low throughout the various phases of the estrous cycle and during most of pregnancy. By contrast, a 4-fold rise in maternal blood acetaldehyde occurred at the end of pregnancy (day 20), continued to increase during lactation (17-fold at day 14) and returned to non-pregnant values after weaning or after pup removal at birth. Both enhanced rate of ethanol oxidation and decreased activity of the low Km aldehyde dehydrogenase in liver mitochondria contributed to the increased acetaldehyde levels. Acetaldehyde was detectable in fetal blood, but only a small fraction of the high maternal values in pregnancy reached the fetus through the umbilical vein. Chronic alcohol administration resulted in decreased fetal size and striking enlargement of the placenta with possible implications for abnormal fetal development. Thus, the high maternal acetaldehyde levels at the end of pregnancy may exert deleterious effects on many maternal organs, including those (such as placenta) which are required for normal fetal development.

Acetaldehyde↗
PubMedDate not supplied

Ferrous sulfate combined with ascorbic acid does not significantly reduce acetaldehyde accumulation in the blood of alcoholized rats treated with disulfiram or betalactam antibiotics.

Adult female SPF Sprague-Dawley rats treated orally by gavage with disulfiram (1 g/kg b.wt.) or betalactam antibiotics (3.38 mmol/kg b.wt.) with a 1-methyltetrazole-5-thiol side chain (cefmenoxime, latamoxef, cefotetan, cefoperazone, cefamandole) produced a marked, statistically significant rise of acetaldehyde in the blood 1 and 3 hr following IP administration of ethanol [2 g/kg b.wt., 20% (g/v) solution]. This accumulation of blood acetaldehyde remained unchanged or was reduced only very slightly by a mixture of iron sulfate [Fe(II)SO4.7H2O, 2.64 mg/kg b.wt.] and ascorbic acid (6.67 mg/kg b.wt.) injected intravenously. This slight decrease is considered to be due to a formation of a complex between ferrous sulfate and agents (disulfiram and the betalactam antibiotics as well as their metabolites) producing acetaldehyde by inhibition of acetaldehyde metabolizing enzymes. A possible coaction of ascorbic acid cannot be explained satisfactorily; ascorbic acid may support cellular redox potentials. The combination of ferrous sulfate and ascorbic acid was used for examination since both chemicals are recommended to reduce adverse symptoms of an ethanol incompatibility reaction in the course of a therapy with the mentioned antibiotics or disulfiram. Since acetaldehyde augmentation in the blood is regarded as a cause of complaints and because the acetaldehyde rise was not depressed significantly by ferrous sulfate and ascorbic acid it can be concluded that these two agents are not potent enough for a rational therapy of ethanol incompatibility symptoms initiated by the investigated drugs.

Acetaldehyde↗