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PubMed1994

Regulation of undulin synthesis and gene expression in human fat-storing cells by acetaldehyde and transforming growth factor-beta 1: comparison with fibronectin.

Undulin and fibronectin (FN) are large extracellular matrix (ECM) glycoproteins possibly involved in cell-matrix interactions. In this study we analyzed the effect of acetaldehyde and transforming growth factor-beta 1 (TGF-beta 1) on undulin and FN synthesis in cultured fat-storing cells (FSC) isolated from wedge sections of normal human livers. Cultured human FSC expressed two mRNA transcripts (6.5 and 8.5 kb) specific for undulin. Acetaldehyde inhibited both undulin mRNA and protein expression, whereas it had an opposite (stimulatory) effect on FN synthesis. TGF-beta 1 induced a dose-dependent increase of both undulin and FN synthesis in FSC cultures. Furthermore, TGF-beta 1 antagonized the inhibitory effect of acetaldehyde on undulin production and potentiated the stimulatory effect of acetaldehyde on FN synthesis. Since undulin is involved in the supramolecular organization of fibrillar collagens and in their enzymatic degradation, its acetaldehyde-induced inhibition may contribute to ECM rearrangement in the early stages of alcoholic liver fibrosis.

Acetaldehyde↗
PubMed1984

Roles of chlorpropamide, alcohol and acetaldehyde in determining the chlorpropamide-alcohol flush.

The value and reproducibility of the chlorpropamide-alcohol flush (CPAF) have been questioned, and objective measures of the test are required. Recording of facial skin temperature, measurement of chlorpropamide, ethanol and acetaldehyde concentrations have been proposed for this purpose. The present study was designed to evaluate the relative contributions of these variables in determining CPAF. Twenty-one Type 2 (non-insulin-dependent) diabetic patients (11 CPAF-positive and 10 CPAF-negative according to previous tests with standard amounts of alcohol and chlorpropamide) were investigated in a random fashion with either chlorpropamide or placebo given on three subsequent evenings before a two-step alcohol challenge with increasing body-weight-matched amounts of alcohol. Higher rises in facial skin temperature and heart rate, higher flush-score and higher acetaldehyde levels resulted from chlorpropamide therapy than followed placebo. After smaller alcohol challenges (with chlorpropamide pretreatment) there were positive intercorrelations between flush-score, rise in facial skin temperature, and plasma concentrations of chlorpropamide and blood acetaldehyde. The increased alcohol dose abolished most of these correlations and a minimum temperature rise of 1.8 degrees C appeared in all but two subjects regardless of previous CPAF classification. During the current experimental conditions, the previously-classified CPAF-positive and CPAF-negative patients did not differ with respect to flush-score, rise in skin temperature, heart rate, blood acetaldehyde or ethanol concentrations, whereas they differed with respect to chlorpropamide concentrations. The present results support the view that CPAF is associated with elevated blood acetaldehyde levels due to inhibition of aldehyde dehydrogenase by chlorpropamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗
PubMed1984

Acetaldehyde utilization and toxicity in Drosophila adults lacking alcohol dehydrogenase or aldehyde oxidase.

Metabolic utilization and toxicity of acetaldehyde were studied in flies lacking alcohol dehydrogenase (ADH), aldehyde oxidase (AO), or both functions. Prior to the experiments, mutant alleles Adhn4 and mal were transferred to the same genetic background by 10 successive backcrosses. By comparison with wild-type flies, various deleterious, pleiotropic effects could be attributed to the mal allele but not to Adhn4. Of the four genotypes studied (mal, Adhn4, mal Adhn4, and wild), all were able to use acetaldehyde as a resource in a similar way. In spite of its high toxicity, acetaldehyde appeared a better resource than ethanol. Flies treated with intermediate acetaldehyde concentrations (around 0.5%) exhibited a very high interindividual heterogeneity which could reflect a physiological adaptation occurring as a consequence of the aldehyde treatment. Toxicity tests showed that ADH-negative flies were more sensitive to acetaldehyde than wild type, but this is most likely explained by the transformation of the aldehyde into alcohol. Our results show that the aldehyde metabolizing enzyme (AME) system in Drosophila is neither ADH nor AO. The existence of an aldehyde dehydrogenase is plausible.

Acetaldehyde↗
PubMed1982

Mitochondrial chemiluminescence elicited by acetaldehyde.

Acetaldehyde-dependent chemiluminescence has been found to be a sensitive technique for the study of superoxide and hydrogen peroxide formation in beef heart mitochondria. The system responds to ATP and antimycin A with increased emission intensities and to ADP and rotenone with decreased intensities, indicating that the chemiluminescence reflects the energy status of the mitochondrion. These effects are based on the ability of acetaldehyde to react with superoxide and hydrogen peroxide to form metastable intermediates which decay spontaneously with the emission of light. Additionally, these intermediates can react with cyanide to give alternative products which can also decay with the emission of light, the cyanide-evokable chemiluminescence. The interaction of acetaldehyde with mitochondria is complex because acetaldehyde can serve as a hydrogen source for NADH and as an inhibitor (at high concentration) of electron transport, and appears to be a reducing agent for a heat-stable site that autoxidatively generates HOOH from O2-.. Inasmuch as acetaldehyde is a metabolite of ethanol, this broad spectrum of reactivity may play a role in the hepatic and cardiac toxicity that is associated with alcoholism. The heat-stable site that generates HOOH from O2-. has been studied further and appears to contain vicinal dithiol which is primarily responsible for the cyanide-evokable chemiluminescence.

Acetaldehyde↗
PubMed2005

Ethanol-induced conditioned place preference, but not aversion, is blocked by treatment with D -penicillamine, an inactivation agent for acetaldehyde.

RATIONALE: There is evidence to suggest that acetaldehyde is involved in the control of ethanol-seeking behavior and reward. D -penicillamine, a thiol amino acid, is a highly selective agent for the inactivation of acetaldehyde. Previous studies from our laboratory have demonstrated that D -penicillamine prevents both behavioral stimulation induced by ethanol and acetaldehyde-produced locomotor depression in mice. OBJECTIVES: The contribution of ethanol-derived acetaldehyde to the affective effects of ethanol (preference and aversion) was assessed using an unbiased place conditioning design. METHODS: Male mice received four pairings of a distinctive floor stimulus (CS+: GRID+ or HOLE+) with injections of saline and ethanol (2 g/kg) given before (preference) or after (aversion) the 5-min exposure to the place conditioning apparatus. A different floor stimulus (CS-: GRID- or HOLE-), associated with saline-saline injections on alternate days, was presented. For a different group of animals, the pairings with the CS+ were associated with saline and ethanol injections, but on alternate days, they received D -penicillamine (50 or 75 mg/kg) and ethanol injections paired with the CS-floor stimulus. A 60-min preference test was carried out 24 h after the last conditioning trial. A similar procedure was followed to test the effect of D -penicillamine on morphine (16 mg/kg) and cocaine-induced (20 mg/kg) conditioned place preference (CPP). RESULTS: CPP and conditioned place aversion (CPA) were observed for ethanol, but D -penicillamine only blocked CPP. D -penicillamine, by itself, did not produce either rewarding or aversive effects. CPP observed for morphine and cocaine was unaffected by D -penicillamine pretreatment. CONCLUSIONS: The results of the present study suggest that the selective inactivation of acetaldehyde blocked the rewarding, but not aversive, effects of ethanol and support the role of this ethanol metabolite in the affective properties of ethanol.

Acetaldehyde↗
PubMed1985

Acetaldehyde: its "disappearance" from human blood.

The reliability of acetaldehyde determination in human blood has often been questioned. Therefore, a new procedure has been worked out consisting of the addition of hydrochloric acid to decrease the disappearance of acetaldehyde, thus allowing the direct determination of acetaldehyde disappearance. The results suggested that the reason for the zero or minimal acetaldehyde concentrations reported by some authors was the consequence of not taking into account the "disappearance" of acetaldehyde from blood.

Acetaldehyde↗
PubMed1991

Acetaldehyde as a substrate for ethanol-inducible cytochrome P450 (CYP2E1).

Liver microsomes from starved and acetone-treated rats catalyzed NADPH-supported metabolism of acetaldehyde at a rate 8-fold higher than corresponding control microsomes; the Vmax was about 6 nmol/mg microsomal protein/min and the apparent Km 30 microM. The reaction was efficiently inhibited by anti-CYP2E1 IgG, but not by control IgG. Reconstituted membranes containing rat CYP2E1 and cytochrome b5 metabolized acetaldehyde with a Vmax of 20 nmol/nmol/min and an apparent Km of 30 microM, whereas CYP2B4 containing vesicles or vesicles without b5 were ineffective. Gas chromatographic/mass spectrometric analysis of products formed from [2H4]-acetaldehyde with CYP2E1-containing reconstituted membrane vesicles revealed the formation of acetate as the only detectable product, although other water soluble products were also formed as evidenced from incubations with [1,2-14C]acetaldehyde. The results indicate that CYP2E1 is an aldehyde oxidase and thus metabolizes both ethanol and its primary oxidation product. This might have implications in vivo for acetaldehyde metabolism in liver and brain.

Acetaldehyde↗
PubMed1984

Oxidation of formaldehyde and acetaldehyde by NAD+-dependent dehydrogenases in rat nasal mucosal homogenates.

Homogenates of respiratory and olfactory tissue from the rat nasal cavity were examined for their capacity to catalyze the NAD+-dependent oxidation of formaldehyde (in the presence and absence of glutathione) and of acetaldehyde. Both aldehydes were oxidized efficiently by nasal mucosal homogenates, and formaldehyde dehydrogenase (FDH) and aldehyde dehydrogenase (AldDH) were tentatively identified in both tissue samples. At least two isozymes of AldDH, differing with respect to their apparent Km and Vmax values with acetaldehyde as substrate, were found in the nasal mucosa, one of which may catalyze the oxidation of both formaldehyde and acetaldehyde. The specific activity of FDH in the olfactory mucosa was twice that in the respiratory mucosa, whereas the specific activity of the higher Km isozyme of AldDH was five to eight times greater in respiratory than in olfactory tissue. The specific activity of the lower Km isozyme of AldDH was similar in respiratory and olfactory homogenates. Repeated exposures of rats to formaldehyde (15 ppm, 6 hr/day, 10 days) or to acetaldehyde (1500 ppm, 6hr/day, 5 days) did not substantially affect the specific activities of FDH and AldDH in nasal mucosal homogenates. Glutathione is a cofactor for FDH; the concentration of nonprotein sulfhydryls in respiratory mucosal homogenates was approximately 2.8 mumoles/g and was not changed significantly by repeated exposures to formaldehyde (15 ppm, 6hr/day, 9 days). These data indicate that the rat nasal mucosa, which is the major target site for both aldehydes in inhalation toxicity studies, can metabolize both formaldehyde and acetaldehyde, and that the specific activities of formaldehyde and aldehyde dehydrogenase in homogenates of the nasal mucosa are essentially unchanged following repeated exposures to toxic concentrations of either compound.

Acetaldehyde↗
PubMed1983

Determination of acetaldehyde in human blood using thiourea to inhibit ethanol interference.

Determination of acetaldehyde in human blood by the semicarbazide method has been studied. An artefactual production of acetaldehyde from ethanol in blood and plasma of about 20 mumol/l was observed at concentrations of ethanol of about 60 mmol/l. This artefact was reduced to less than 1 mumol/l after addition of thiourea. The presumably non-enzymatic production of acetaldehyde from ethanol was demonstrated by the release of 3H from (1R)-[3H]ethanol added to the blood immediately after sampling. The results demonstrate that oxidation of ethanol is the major cause of the artefactual acetaldehyde formation. In human volunteers, metabolising ethanol, very low concentrations of acetaldehyde were found by the modified method, which includes thiourea.

Acetaldehyde↗
PubMed1985

Dual effects of acetaldehyde on electrical activity in the isolated frog spinal cord.

Acetaldehyde (1.4 X 10(-7)-1.4 X 10(-5) M) produced a transient depolarization followed by a distinct hyperpolarization of the ventral and dorsal roots as recorded by sucrose-gap in the isolated spinal cord. This effect occurred more frequently at lower concentrations than at higher concentrations of acetaldehyde, and the depolarization increased with doses increasing. The ventral root reflex potentials evoked by the dorsal root stimulation had decreased amplitudes during depolarization and increased during hyperpolarization. In the presence of Mg2+ or tetrodotoxin, acetaldehyde produced only hyperpolarization. Acetaldehyde slightly prolonged glutamate-induced depolarization of both roots. These results suggest that acetaldehyde acts not only on the spinal motoneuron resulting in membrane hyperpolarization but also on the presynaptic sites, which causes postsynaptic membrane depolarization probably through an increased release and decreased uptake or inactivation of the excitatory transmitter.

Acetaldehyde↗
PubMed1992

Immunoglobulin A antibody to a 200-kilodalton cytosolic acetaldehyde adduct in alcoholic hepatitis.

Considerable clinical and experimental evidence points to the importance of immune responses in the development of alcoholic liver disease. In the present study it was investigated whether circulating antibodies from patients with alcoholic liver disease recognize acetaldehyde-liver protein adducts. Cytosolic and microsomal fractions from livers of Wistar rats or from normal human liver were incubated with acetaldehyde (0.5-2.5 mmol/L) and/or cyanoborohydride (100 mmol/L) then analysed by immunoblotting. Cytosolic fractions that had been incubated with acetaldehyde and cyanoborohydride expressed a 200-kilodalton protein antigen not present in untreated fractions or fractions incubated with acetaldehyde or cyanoborohydride alone. The 200-kilodalton antigen was recognized by immunoglobulin (Ig)A antibodies in a large proportion of sera from patients with alcoholic hepatitis (70%, n = 23), but in significantly smaller proportions of sera from patients with alcoholic cirrhosis without hepatitis (30%, n = 10; P < 0.05), heavy drinkers without overt liver disease (20%, n = 10; P < 0.02), patients with nonalcoholic liver disease (35%, n = 17; P < 0.05), or normal control subjects consuming moderate quantities of alcohol (25%, n = 20%; P < 0.005). These results indicate that IgA antibodies to a 200-kilodalton acetaldehyde-protein adduct are present in a large proportion of patients with alcoholic liver disease and in a significantly smaller proportion of other individuals.

Acetaldehyde↗
PubMed1986

Alcohol and acetaldehyde in rat's milk following ethanol administration.

Alcohol and acetaldehyde were measured in milk and peripheral blood in chronic alcoholic rats, at 5 and 15 days of lactation. Ethanol in blood increased throughout lactation and the levels of acetaldehyde were much higher than in nonlactating alcoholic rats. The concentration of acetaldehyde in milk was always ca. 50% of that in blood, whereas that of ethanol varied within the range of 44-80% of the blood levels. Blood alcohol levels in the corresponding sucking pups were much lower than in maternal blood and increased throughout lactation. The time course of ethanol and acetaldehyde concentration in blood and milk were determined in normal lactating rats after cyanamide (40 mg/kg) and ethanol administration (2 or 4 g/kg). Milk alcohol reached higher concentrations than in blood within the first hour of ethanol administration, decreasing and remaining constant thereafter at ca. 65% of those in blood. Acetaldehyde levels in milk were always 35-45% lower than in blood. No alcohol dehydrogenase activity was found in homogenates of mammary tissue; however there was some aldehyde dehydrogenase activity. A significant decrease in mammary tissue aldehyde dehydrogenase was found in chronic alcoholic rats. The role of this enzyme is discussed.

Acetaldehyde↗
PubMed1987

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice is enhanced by ethanol or acetaldehyde.

Persistent neurochemical changes consistent with parkinsonism have been reported in brains of mice treated with repeated high doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We now report that ethanol or acetaldehyde potentiate MPTP-induced damage to mouse striatum. One hour after the combined treatments (ethanol and MPTP or acetaldehyde and MPTP), the animals exhibited a marked and long-lasting catatonic posture and then returned gradually to apparently normal locomotion. Seven days after MPTP administration, depletion of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in mouse striatum were further potentiated in the group of animals treated with ethanol. This effect was more evident when the treatment was repeated twice and was dose-dependent. Acetaldehyde was more potent than ethanol in enhancing MPTP neurotoxicity. A single exposure to acetaldehyde before and during MPTP treatment produced a very consistent fall of DA, DOPAC and HVA but not serotonin (5HT) or 5-hydroxyindoleacetic acid (5HIAA) in the striatum. This suggests that ethanol effects on MPTP neurotoxicity might be related to acetaldehyde formation.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Acetaldehyde binding increases the catabolism of rat serum low-density lipoproteins.

Acetaldehyde was found to form adducts with rat serum lipoproteins. The binding of [14C]acetaldehyde to lipoproteins was studied at low concentrations which are known to exist during ethanol oxidation. The amount of lipoprotein adducts was a linear function of acetaldehyde concentration up to 250 microM. Incubation of rat plasma low-density lipoproteins (LDL) with 200 microM acetaldehyde increased the disappearance rate of the 3H-label from the cholesterol ester moiety of LDL injected into normal rats. The data show that even low concentrations of acetaldehyde are capable of affecting LDL metabolism. These findings may provide an explanation for the low concentrations of serum LDL in alcoholics.

Acetaldehyde↗
PubMed1990

Impairment of histone H1 DNA binding by adduct formation with acetaldehyde.

Incubation of histone H1 with pharmacologically relevant concentrations of acetaldehyde resulted in the formation of spontaneously stable acetaldehyde-protein linkages. The reaction of acetaldehyde and H1 purified from rat liver either by a DNA recognition site affinity chromatography or by perchloric acid extraction occurred primarily at the lysine residues in the carboxyterminal tail of H1, which is crucial for its function as a eukaryotic repressor. It was further shown using an H1-lacZ fusion protein produced in E. coli and the protein isolated from rat liver that the formation of acetaldehyde adducts with H1 impair its DNA binding properties. We propose that such a reaction may occur in vivo and lead to an inability to repress genes in the liver upon excessive alcohol consumption. This mechanism may play a role in acetaldehyde-induced collagen synthesis in alcoholics.

Acetaldehyde↗
PubMed1981

Effects of ethanol and acetaldehyde on the rat adrenal.

A pseudoCushing syndrome, indistinguishable from true Cushing syndrome except that it disappears with abstinence from alcohol, is known to occur in alcoholics. An animal model was used to study this syndrome in vitro, as earlier studies have shown that ethanol administration to animals increases corticosterone secretion. Such secretion appears to be the result of ethanol-induced ACTH secretion. We have examined the effects of ethanol and acetaldehyde on the production of three steroids: corticosterone, progesterone, and androstenedione in the isolated perfused rat adrenal. The adrenal glands and left kidney of rats were perfused with medium and one of the following additions: ethanol, acetaldehyde, ACTH or ACTH with either ethanol or acetaldehyde. The amount of the three steroids in the adrenal and the perfusion effluent was determined and compared to that of nonperfused adrenal glands. We found that perfusion with medium alone increased the production of each steroid (p less than 0.05) in the presence of ethanol or acetaldehyde. Assay of the medium before and after perfusion showed no ACTH, so that the increased steroid production cannot be ascribed to ACTH contamination. Furthermore, the addition of ACTH to perfusion medium which contained ethanol or acetaldehyde did not further enhance the responses.

Acetaldehyde↗
PubMed1989

A comparative study on ethanol and acetaldehyde as inducers of chromosome malsegregation in Aspergillus nidulans.

The activity of ethyl alcohol and acetaldehyde on mitotic chromosome segregation and conidial germination in Aspergillus nidulans was studied. Ethanol effectively induced malsegregation in a narrow range of concentrations (4.5-5.5%, v/v) and was inactive at doses which arrested conidial germination (above 6%). The same bell-shaped dose-response curve was shown by the spindle poison chloral hydrate, which was active in the range 6-10 mM. Acetaldehyde displayed a diphasic dose-response curve. Genetic analysis of induced segregants suggests that the disturbance of chromosome segregation is the primary genetic effect at low doses (0.025-0.037%), while at higher doses (above 0.1%), when growth was arrested, chromosome damage was primarily induced. The same pattern of segregants was produced by hydroquinone, a substance which indirectly affects chromosome segregation in A. nidulans. These differences in the genotoxic profiles of ethanol and acetaldehyde suggest that the effect exerted by ethanol on A. nidulans mitosis is not dependent on its conversion into acetaldehyde. In the absence of an effect of ethanol on in vitro polymerization of tubulin (actively inhibited by acetaldehyde at doses above 0.075%), a direct effect of ethanol on cell membranes is hypothesized. Comparison of the inhibition of growth and the effectiveness in aneuploidy induction displayed by ethanol, methanol, n-propanol and n-butanol demonstrates, in fact, a fair correlation with logP, a descriptor of lipophilicity related to the partitioning of compounds in biological membranes.

Acetaldehyde↗
PubMed1984

Effects of naloxone and buprenorphine on intravenous acetaldehyde self-injection in rats.

Rats can be induced to self-inject acetaldehyde under an appropriate operant conditioning schedule. The narcotic antagonist naloxone (30 mg/kg) is shown to produce a decrease in schedule-induced acetaldehyde self-injection, but was without effect on both barpress responding and spontaneous activity in rats tested individually for fine, gross and total activity. On the other hand buprenorphine (0.3 and 3 mg/kg), the mixed agonist-antagonist derived from the opium alkaloid thebaine, also produced a significant decrease in acetaldehyde self-injection. However, a significant effect of buprenorphine on barpressing in otherwise drug naive rats indicated that this finding should not be dissociated from a possible involvement of buprenorphine on motor responding. While the findings are consistent with the hypothesis of opiate involvement in acetaldehyde self-administration, caution must be exercised when drawing conclusions about the participation of endogenous opiates in acetaldehyde-mediated behavior.

Acetaldehyde↗