Lowering of Blood Acetaldehyde but Not Ethanol Concentrations by Pantethine following Alcohol Ingestion: Different Effects in Flushing and Nonflushing Subjects

A rise in blood acetaldehyde concentrations following alcohol ingestion was significantly inhibited when healthy nonflushing subjects were administered a clinical dose of pantethine orally. However, similar findings were not observed in flushing (alcohol-sensitive) subjects lacking hepatic low Km aldehyde dehydrogenase (ALDH). The blood ethanol concentrations were not altered by this treatment in either flushing or nonflushing subjects. Acetaldehyde (45 microM) added in vitro to whole blood and plasma obtained 1 hr after pantethine administration disappeared as the incubation continued similarly as with blood and plasma obtained prior to pantethine treatment. Pantethine-related metabolites, such as taurine, pantetheine, coenzyme A, and pantothenate, activated ALDH in vitro. Hepatic acetaldehyde levels following ethanol loading of rats treated with pantethine were much lower than in untreated rats. The pantethine action observed only in nonflushing subjects might be due to an accelerated oxidation of acetaldehyde by the activation of low Km ALDH by pantethine-related metabolites formed in the liver.     

Exaggerated Acetaldehyde Response after Ethanol Administration during Pregnancy and Lactation in Rats

The exaggerated blood acetaldehyde response that has been reported after ethanol administration to pregnant rats was found to be the beginning of a much larger alteration occurring during lactation. Indeed, at the end of pregnancy, we confirmed a 4-fold increase in the acetaldehyde values above nonpregnant values after an intragastric dose of 3 g/kg ethanol. During gestational days 1 to 17, the levels did not differ. After delivery, the exaggerated acetaldehyde response to ethanol was increased, producing acetaldehyde concentrations 15-fold greater than in nonlactating controls. This response returned to nonpregnant levels with weaning and could be abolished by removing the pups at birth. The intensified response was associated with both an enhanced rate of ethanol oxidation and a decreased low Km aldehyde dehydrogenase activity in liver mitochondria. At the end of pregnancy, measurable concentrations of acetaldehyde were found in umbilical venous blood and fetal blood. However, they amounted to only one-quarter of maternal values whereas ethanol levels were similar. Thus, during late pregnancy and lactation, there is a marked increase in maternal blood acetaldehyde after ethanol intake. In the presence of a normal placenta, however, an acetaldehyde concentration gradient exists between the mother and the fetus.     

Impaired acetaldehyde metabolism in patients with non-alcoholic liver disorders.

In order to determine the specificity of abnormalities of alcohol metabolism in patients with alcoholic liver disease, blood acetaldehyde concentrations after oral ethanol challenge and the activities of alcohol metabolising enzymes in liver biopsy samples have been determined in patients with alcoholic liver disease and a wide variety of non-alcoholic liver disorders. Significant decreases in hepatic cytosolic aldehyde dehydrogenase activity were associated with significant increases in acetaldehyde concentrations after ethanol in both patient groups compared with control subjects. There was a significant correlation between hepatic cytosolic aldehyde dehydrogenase and mean blood acetaldehyde concentration 30-180 min after ethanol ingestion (y = 17.4-0.45x; r = -0.56; p less than 0.01) confirming the importance of this enzyme in controlling blood acetaldehyde concentrations. These findings suggest that disturbances in alcohol metabolism in patients with alcoholic liver disease are the consequence of liver damage rather than a specific abnormality predisposing to alcohol induced liver injury.     

Determinants of Ethanol and Acetaldehyde Metabolism in Chronic Alcoholics

We have studied the factors determining the rate of ethanol and acetaldehyde metabolism in a group of 25 alcoholics with varying degrees of liver lesion (from normal liver to cirrhosis) and in six nonalcoholic cirrhotics. In alcoholics the ethanol metabolic rate was related to hepatic function, estimated either by the aminopyrine breath test ( r = 0.70, p < 0.001) or the indocyanine green clearance ( r = 0.76, p < 0.01), and was independent of the activity of hepatic alcohol dehydrogenase and hepatic blood flow. In nonalcoholic cirrhotics blood acetaldehyde was always below the detection limit (0.5 μM), but elevated levels were found in 14 out of the 25 alcoholics. Alcoholics with elevated blood acetaldehyde showed a significantly higher ethanol metabolic rate than alcoholics with undetectable acetaldehyde (120 ± 17 mg/kg/hr vs 104 ± 11 mg/kg/hr, p < 0.02), but no differences were observed in the activities of alcohol and aldehyde dehydrogenases. Peak blood acetaldehyde levels were directly related to the ethanol metabolic rate ( r = 0.48, p < 0.02), but not to activities of hepatic alcohol or aldehyde dehydrogenases. These results indicate that in chronic alcoholics the main determinant of the ethanol metabolic rate is hepatic function, while the rise of blood acetaldehyde is mainly dependent on the ethanol metabolic rate. Alcohol and aldehyde dehydrogenase activities do not seem to be rate-limiting factors in the oxidation of ethanol or acetaldehyde.     

Determinants of Blood Acetaldehyde Level during Ethanol Oxidation in Chronic Alcoholics

We analyzed the blood alcohol and acetaldehyde concentrations in nine alcoholics and four healthy nonalcoholic controls during and after an intravenous infusion of a high and a low dose of alcohol. In the alcoholics, the mean rates of plasma ethanol disappearance were significantly higher than in nonalcoholic controls. In the control subjects, the blood acetaldehyde levels were, in general, below the detection limit (less than 0.5 microM), but in sharp contrast to this, an elevated blood acetaldehyde during ethanol infusion was found in 6/9 alcoholics. Peak blood acetaldehyde values were higher after the high than the low dose of alcohol. Fructose infusion significantly enhanced the rate of plasma ethanol disappearance both in controls and in alcoholics, and this was usually associated with a significant elevation of blood acetaldehyde level. The maximal specific activities (expressed as milliunits/mg og protein) of alcohol, lactate, and aldehyde dehydrogenases in liver were significantly lower in alcoholics than in controls. Even more importantly, the peak blood acetaldehyde correlated negatively with the activity of hepatic "low-Km" aldehyde dehydrogenase. Our results suggest that the main reason for blood acetaldehyde elevation seen in these chronic alcoholics is their impaired capacity to metabolize acetaldehyde. This may be further accentuated by the increased rate of ethanol oxidation.     

Alcohol Preference and Hepatic Alcohol Dehydrogenase Activity in Adult Long-Evans Rats is Affected by Intrauterine Sibling Contiguity

Alcohol preference and hepatic alcohol dehydrogenase activity in adult rats are known to be sexually dimorphic. Intrauterine sibling contiguity (the intrauterine position of a fetus relative to adjacent siblings of the same or opposite sex) alters selected reproductive, behavioral and enzymatic sexual dimorphisms via intersibling sex hormone transfer. We postulated that sibling contiguity would affect alcohol preference and hepatic alcohol metabolism in adult rats. The results of our study demonstrate that adult mMm male Long-Evans rats (genetic male rat developing in utero between two male siblings) had significantly lower ethanol preference, attained higher blood alcohol levels after standard ethanol "challenge" doses and had significantly lower hepatic alcohol dehydrogenase activity than either male siblings developing in utero between two females (fMf) or genetic females developing between two males or between two females (mFm or fFf). Hepatic cytosolic aldehyde dehydrogenase activity was higher in adult female than male rats regardless of nearest neighbor siblings. It is suggested that the differences in ethanol preference and hepatic alcohol dehydrogenase activity between the adult mMm and fMf male rats is due to differences in prenatal hormonal environment which can modulate sexual dimorphisms in alcohol intake and metabolism in the adult.     

Disposition of Ethanol and Activity of Hepatic and Placental Alcohol Dehydrogenase and Aldehyde Dehydrogenases in the Third-Trimester Pregnant Guinea Pig for Single and Short-Term Oral Ethanol Administration

The disposition of ethanol and its metabolite, acetaldehyde, and the activity of alcohol dehydrogenase (ADH) and aldehyde dehydrogenases (ALDH) were determined in the third-trimester pregnant guinea pig following single and 7-day oral administration of ethanol (0.5 g X kg maternal body weight-1 X day-1). Animals were killed at each of selected times after the single and seventh ethanol dose. For both ethanol dosage regimens, the maternal and fetal blood and brain ethanol concentrations were virtually identical during the elimination phase of the time-course study. There was initial slow transfer of ethanol into amniotic fluid, followed by significantly higher ethanol concentration in amniotic fluid relative to maternal and fetal blood during the elimination phase. Acetaldehyde was measurable in maternal blood, maternal brain, and fetal brain at concentrations that were low and variable. For both ethanol dosage regimens, ADH activity was measurable only in maternal liver. Low Km ALDH activity was measurable only in maternal liver and fetal liver. High Km ALDH was measurable in maternal liver, fetal liver, and placenta and was significantly greater in maternal liver. The data indicate that there is bidirectional placental transfer of ethanol in the maternal-fetal unit; the elimination of ethanol from the maternal and fetal compartments is regulated by maternal hepatic biotransformation involving ADH; the amniotic fluid is a reservoir for ethanol in utero; the low Km ALDH in fetal liver protects the fetus from ethanol-derived acetaldehyde in the maternal circulation; and short-term maternal administration of once-daily, low-dose ethanol does not produce major changes in ethanol disposition and the activity of the enzymes involved in ethanol biotransformation.     

Relationship of brain ethanol metabolism to the hypnotic effect of ethanol. II: Studies in selectively bred rats and mice

BACKGROUND: To clarify the role of brain acetaldehyde in the hypnotic effect of ethanol, we compared the ethanol-oxidizing capacity (rate of acetaldehyde accumulation) and catalase and aldehyde dehydrogenase activity in the brains of animals genetically selected for different sensitivities to the hypnotic effect of ethanol. METHODS: We used high, low, or control alcohol-sensitive rats (HAS, LAS, and CAS) and short- and long-sleep mice (SS and LS), as well as SS x LS recombinant inbred mice with known strain differences in mean duration of ethanol-induced sleep. We studied the rate of accumulation of acetaldehyde from ethanol in brain homogenates of these animals and correlated those values with their hypnotic sensitivity to ethanol. RESULTS: Acetaldehyde accumulation from ethanol was significantly higher in the brain homogenates from HAS rats and LS mice with high sensitivity to the hypnotic effect of ethanol in vivo, compared with LAS rats and SS mice with low sensitivity to ethanol. A correlation was found between the duration of ethanol-induced sleep and the in vitro rate of accumulation of ethanol-derived acetaldehyde in the brains of recombinant SS x LS mice strains. There was no correlation of sleep time with brain catalase levels. There were no line differences in brain catalase or aldehyde dehydrogenase or in alcohol or aldehyde dehydrogenase activity in livers of LAS, CAS, and HAS rats or in SS and LS mice. CONCLUSIONS: A correlation between the brain acetaldehyde accumulation, but not catalase levels, and the central effect of ethanol was demonstrated in animals genetically differing in initial sensitivity to the hypnotic effect of ethanol.     

Genetic polymorphism of human liver alcohol and aldehyde dehydrogenases, and their relationship to alcohol metabolism and alcoholism

It is now widely accepted that the various pharmacologic and addictive consequences of alcohol consumption are related to the tissue concentration of ethanol or its metabolic products. The oxidative metabolism of ethanol in liver is principally catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase. Both of these enzymes exist in multiple molecular forms, and genetic models have been proposed to account for the multiplicity of isoenzymes. Alcohol dehydrogenase subunits are encoded at five different gene loci, and genetic polymorphism occurs at two alcohol dehydrogenase loci. Variant isoenzymes produced at the two polymorphic alcohol dehydrogenase loci account for the differences in enzyme electrophoretic patterns observed among individuals. Some of these variant isoenzymes exhibit widely different kinetic properties, and this may account for the 2- to 3-fold variation in alcohol elimination rate among individuals. Since the protein sequence of several of the alcohol dehydrogenase subunits has been determined and several of the alcohol dehydrogenase genes has been cloned, some of the structural changes which give rise to differences in catalytic and electrophoretic properties are now known. Genetic polymorphism also occurs at the aldehyde dehydrogenase gene locus which encodes the mitochondrial low Km for acetaldehyde aldehyde dehydrogenase isoenzyme. The variant isoenzyme exhibits little or no catalytic activity. Individuals with this "null" variant have higher than normal blood acetaldehyde levels and exhibit an alcohol-flush reaction which appears to be a deterrent to heavy drinking and alcoholism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Genetic variability of enzymes of alcohol metabolism in human beings

Alcohol is eliminated from the body almost entirely by hepatic metabolism, first to acetaldehyde, then to acetate, and finally to carbon dioxide and water. The time course of elimination is best described by Michaelis-Menten kinetics, and rates of elimination following standard doses of ethanol vary among subjects as much as three-fold. Studies comparing rates of elimination in identical and fraternal twins have shown that about half of the variability is attributable to genetic factors. The principal enzymes responsible for ethanol metabolism are alcohol dehydrogenase and aldehyde dehydrogenase. The reaction catalyzed by alcohol dehydrogenase is the rate-limiting step of the pathway. Human livers contain multiple isoenzymes of alcohol dehydrogenase, which are dimeric molecules arising from the association of two subunits encoded by five different structural genes. Genetic polymorphism at two of these gene loci has been described, and all known homo- and heterodimeric forms of the isoenzymes have now been isolated and characterized. Notably, some of them differ quite strikingly in reactivity toward ethanol. Thus a basis for the genetic variability in alcohol metabolic rate can be found in the kinetic properties of the alcohol dehydrogenase isoenzymes. The efficient oxidation of acetaldehyde by hepatic aldehyde dehydrogenase is essential for ethanol oxidation to continue over time, because the equilibrium of the alcohol dehydrogenase reaction favors the conversion of acetaldehyde to ethanol. Acetaldehyde is a very toxic substance the removal of which makes possible the consumption of large quantities of ethanol frequently imbibed by alcoholics. There are also multiple molecular forms of aldehyde dehydrogenase in liver, and the mitochondrial form is the one principally responsible for acetaldehyde oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acetaldehyde Metabolism in Different Aldehyde Dehydrogenase-2 Genotypes

In order to clarify the relationships between acetaldehyde (Ac-CHO) metabolism and low Km (mitochondrial) aldehyde dehydrogenase (ALDH2) genotypes, hepatic ALDH2 activity was determined and serial changes of blood Ac-CHO levels after ethanol administration were analyzed in the individuals homozygous for the normal ALDH2 genes, heterozygous for the normal and mutant ALDH2 genes, and homozygous for the mutant ALDH2 genes. Genomic DNA was extracted from white blood cells and genotyping of ALDH2 was performed using the polymerase chain reaction technique and slot blot hybridization with synthesized oligonucleotide probes specific to the normal and mutant ALDH2 genes. ALDH2 activity was not detectable in the liver in two cases of the mutant homozygote. In four out of eight cases of the heterozygote, hepatic ALDH2 activity was measurable, although the activity was lower compared with that in the normal homozygote. Blood ethanol levels after alcohol administration were not different among the three different ALDH2 genotypes. Blood Ac-CHO levels after drinking of alcohol were significantly higher in the heterozygotes and the mutant homozygotes than in the normal homozygotes. The levels after a moderate amount of ethanol (0.8 g/kg of body weight) in a case of the mutant homozygote were not different from those of the heterozygotes. However, the levels after a small amount of ethanol (0.1 g/kg of body weight) were significantly higher in the mutant homozygotes than in the heterozygotes. These results indicate that hepatic ALDH2 activity is lacking completely, and metabolism of Ac-CHO in the liver is severely impaired in the homozygotes of the mutant ALDH2 genes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aldehyde dehydrogenase 2 gene targeting mouse lacking enzyme activity shows high acetaldehyde level in blood, brain, and liver after ethanol gavages

BACKGROUND: Previously, we created an aldehyde dehydrogenase 2 gene transgenic (Aldh2-/-) mouse as an aldehyde dehydrogenase (ALDH) 2 inactive human model and demonstrated low alcohol preference. In addition, after a free-choice drinking test, no difference in the acetaldehyde level was observed between the Aldh2-/- and wild type (Aldh2+/+) mice. The actual amounts of free-choice drinking were so low that it is uncertain whether these levels are pharmacologically and/or behaviorally relevant in either strain. To elucidate this uncertainty, we compared the ethanol and acetaldehyde concentration in the blood, brain, and liver between the Aldh2-/- and Aldh2+/+ mice after ethanol gavages at the same dose and time. METHOD: We measured differences in the ethanol and acetaldehyde levels between the Aldh2-/- and Aldh2+/+ mice by headspace gas chromatography-mass spectrometry (GC-MS) after ethanol gavages at the same dose and time. RESULTS: Significantly higher blood acetaldehyde concentrations were found in the Aldh2-/- mice than in the Aldh2+/+ mice 1 hr after the administration of ethanol gavages at doses of 0.5, 1.0, 2.0, and 5.0 g/kg. The blood acetaldehyde concentrations in the two strains were 2.4 vs. 0.5, 17.8 vs. 1.9, 108.3 vs. 4.3, and 247.2 vs. 14.0 (microM), respectively. In contrast, no significant difference was observed in the blood ethanol concentrations between the Aldh2+/+ and Aldh2-/- mice. The aldehyde dehydrogenase 2 enzyme metabolized 94% of the acetaldehyde produced from the ethanol as calculated from the area under the curve (AUC) of acetaldehyde when ethanol was administered at a dose of 5.0 g/kg. CONCLUSIONS: These data indicate that mouse ALDH2 is a major enzyme for acetaldehyde metabolism, and the Aldh2-/- mice have significantly high acetaldehyde levels after ethanol gavages.     

Aldehyde dehydrogenase in alcoholic subjects

Hepatic aldehyde dehydrogenase activity is depressed in alcoholic liver disease and may account for the observation that alcoholics develop high blood acetaldehyde concentrations following ethanol. To determine whether this is a specific defect in alcoholics, aldehyde dehydrogenase was studied in liver tissue obtained from three groups of subjects. Group I comprised 30 patients with alcoholic liver disease, Group II consisted of eight subjects with liver disease unrelated to alcohol abuse and Group III was a control group of 10 individuals with no significant liver disease. Mean hepatic aldehyde dehydrogenase activity was significantly lower in Group I than in Groups II or III [4.9 +/- 0.6 (mean +/- S.E.), compared to 10.2 +/- 1.8 and 12.4 +/- 1.1 nmoles of acetaldehyde oxidized per min X mg of protein, respectively]. Aldehyde dehydrogenase activity in Group II was relatively well maintained. Aldehyde dehydrogenase activity was found in cytosolic and mitochondrial fractions of liver homogenates. In alcoholic subjects, cytosolic aldehyde dehydrogenase activity was not more depressed than was mitochondrial aldehyde dehydrogenase. Isoelectric focusing demonstrated a single mitochondrial isoenzyme and a single cytosolic isoenzyme in most cases in Group III. In contrast, multiple cytosolic isoenzymes were consistently found in liver tissue from Group I subjects. These findings suggest that depressed aldehyde dehydrogenase activity in alcoholic subjects is not a consequence of liver disease.     

Human Blood Acetaldehyde Levels: With Improved Methods, a Clearer Picture Emerges

New reliable methods for the determination of acetaldehyde in human blood, either from separated plasma or from acid-precipitated whole blood, demonstrate that the blood of healthy Caucasians contains at most only extremely small amounts of acetaldehyde (less than 1 microM) after moderate alcohol intoxication. On the other hand, among about 50% of the Japanese population ethanol ingestion results in elevated blood acetaldehyde levels (10-50 microM) with consequent unpleasant cardiovascular responses such as facial flushing and tachycardia, apparently because of a lack of one of the acetaldehyde-oxidizing aldehyde dehydrogenase isozymes. Elevated acetaldehyde levels may eventually occur also among intoxicated Caucasian alcoholics, primarily as a consequence of abuse-induced loss of hepatic aldehyde dehydrogenase activity, but accentuated by an accelerated ethanol oxidation rate. The elevation is probably reversible, since no acetaldehyde is seen in alcoholics after abstinence and hospital treatment. There is thus little evidence that an elevation of acetaldehyde could serve as a marker for predisposition for alcoholism.     

Racial Differences in Biological Sensitivity to Ethanol: The Role of Alcohol Dehydrogenase and Aldehyde Dehydrogenase Isozymes

Electrophoretic and kinetic studies of autopsy liver specimens from individuals of different racial groups revealed a polymorphism in alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). About 85% of the Japanese livers had an atypical ADH and 52% of the livers an unusual ALDH. Only 13% of German liver specimens had the atypical ADH and none showed the unusual form of ALDH which lacks in the isozyme with low Km for acetaldehyde. Using hair roots as the source of ADH and ALDH, individuals showing sensitivity to ethanol were examined. Data on the distribution of phenotypes in random European and Japanese population as well as family studies suggest a direct relationship between the lack of low Km isozyme of ALDH and alcohol-induced biological sensitivity. Our findings suggest that the alcohol sensitivity quite common in individuals of Mongoloid origin might be due to delayed oxidation of acetaldehyde by an unusual type of ALDH.     

Intralobular Distribution of Class I Alcohol Dehydrogenase and Aldehyde Dehydrogenase 2 Activities in the Hamster Liver

The hepatic lobular localization of class I alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) 2 activities was examined histochemically using livers of hamsters with high ethanol preferences. The activity of class I ADH detected by the nitro blue tetrazolium method using 5 mM ethanol as a substrate was extremely high and was almost homogeneously distributed throughout the lobule. The ALDH 2 activity (substrate, 8 μM acetaldehyde) was localized to the centrilobular zone, whereas low K_m ALDH (ALDH 1 + ALDH 2) activity (substrate, 50 μM acetaldehyde) showed a gradient distribution in the lobule with high centrilobular to moderate periportal activity, suggesting that the ALDH 1 activity was distributed throughout the lobule.     

Antipyrine and Aminopyrine Induce Acetaldehyde Accumulation from Ethanol in Isolated Hepatocytes

The addition of antipyrine or aminopyrine to isolated hepatocytes derived from normal rats and incubated with ethanol caused a significant decrease in the oxidation of ethanol to acetate. This decrease was associated with a corresponding accumulation of acetaldehyde. The degree of inhibition with each drug was concentration-dependent, and there was a lag phase before inhibition of acetate formation and acetaldehyde accumulation became apparent. These effects were augmented in cells isolated from phenobarbital-treated rats, and the lag phase was reduced, implying that the effects of both drugs were dependent on their cytochrome P–450-mediated metabolism. The addition of the cytochrome P-450 inhibitor, cimetidine, significantly reduced the amount of acetaldehyde accumulating from ethanol when hepatocytes were incubated with either antipyrine or aminopyrine. Neither drug added directly to mitochondrial extracts inhibited the activity of aldehyde dehydrogenase. However, when neutralized extracts of hepatocytes that had undergone a 40-min incubation with ethanol and each drug were added to mitochondrial extracts, aldehyde dehydrogenase activity was substantially decreased. A greater inhibition was observed with neutralized extracts of hepatocytes from phenobarbital-treated rats. The results suggest that cytochrome P-450-generated metabolites of antipytine and aminopyrine cause an inhibition of the low K_m mitochondrial aldehyde dehydrogenase and thus an accumulation of acetaldehyde from ethanol.     

Metronidazole increases intracolonic but not peripheral blood acetaldehyde in chronic ethanol-treated rats

BACKGROUND: Metronidazole leads to the overgrowth of aerobic flora in the large intestine by reducing the number of anaerobes. According to our previous studies, this shift may increase intracolonic bacterial acetaldehyde formation if ethanol is present. Metronidazole is also reported to cause disulfiram-like effects after alcohol intake, although the mechanism behind this is obscure. Therefore, the aim was to study the effect of long-term metronidazole and alcohol treatment on intracolonic acetaldehyde levels and to explore the possible role of intestinal bacteria in the metronidazole related disulfiram-like reaction. METHODS: A total of 32 rats were divided into four groups: controls (n = 6), controls receiving metronidazole (n = 6), ethanol group (n = 10), and ethanol and metronidazole group (n = 10). All rats were pair-fed with the liquid diet for 6-weeks, whereafter blood and intracolonic acetaldehyde levels and liver and colonic mucosal alcohol (ADH) and aldehyde dehydrogenase (ALDH) activities were analyzed. RESULTS: The rats receiving ethanol and metronidazole had five times higher intracolonic acetaldehyde levels than the rats receiving only ethanol (431.4 +/- 163.5 microM vs. 84.7 +/- 14.4 microM,p = 0.0035). In contrast, blood acetaldehyde levels were equal. Cecal cultures showed the increased growth of Enterobacteriaceae in the metronidazole groups. Metronidazole had no inhibitory effect on hepatic or colonic mucosal ADH and ALDH activities. CONCLUSIONS: The increase in intracolonic acetaldehyde after metronidazole treatment is probably due to the replacement of intestinal anaerobes by ADH-containing aerobes. Unlike disulfiram, metronidazole neither inhibits liver ALDH nor increases blood acetaldehyde. Thus, our findings suggested that the mechanism behind metronidazole related disulfiram-like reaction might be located in the gut flora instead of the liver.     

Influence of aging on ethanol and acetaldehyde oxidation in female rat liver

Rates of ethanol metabolism by alcohol dehydrogenase, the microsomal ethanol oxidizing system (MEOS), and catalase were similar in liver preparations from young (4-5 months) and old (24-27 months) female Fischer 344 rats. On the other hand, rates of acetaldehyde metabolism by mitochondrial aldehyde dehydrogenase (ALDH) were 15-20% lower in livers of old rats than in those of younger ones. Results with the ALDH inhibitor cyanamide indicated that a decline in ALDH activity of this magnitude would not increase acute ethanol hepatotoxicity.     

Inhibition of rat hepatic mitochondrial aldehyde dehydrogenase-mediated acetaldehyde oxidation by trans-4-hydroxy-2-nonenal

The hepatic oxidation of ethanol has been demonstrated to cause peroxidation of cellular membranes, resulting in the production of aldehydes that are substrates for hepatic aldehyde dehydrogenases. It was the purpose of this study to evaluate the cooxidation of the lipid peroxidation product, trans-4-hydroxy-2-nonenal, and acetaldehyde by high-affinity mitochondrial aldehyde dehydrogenase, which is of prominent importance in the oxidation of ethanol-derived acetaldehyde. Experiments were performed for determination of kinetic parameters for uninhibited acetaldehyde and 4-hydroxynonenal oxidation by semi-purified mitochondrial aldehyde dehydrogenase prepared from male Sprague-Dawley rat liver. The affinity of the enzyme for the substrate at low substrate concentrations and the Michaelis-Menten constant of mitochondrial aldehyde dehydrogenase for acetaldehyde were 25 and 10 times greater, respectively, than those determined for 4-hydroxynonenal. Coincubation of acetaldehyde with physiologically relevant concentrations of 4-hydroxynonenal (0.25 to 5.0 mumol/L) with mitochondrial aldehyde dehydrogenase demonstrated that 4-hydroxynonenal is a potent competitive or mixed-type inhibitor of acetaldehyde oxidation, with concentration of 4-hydroxynonenal required for a twofold increase in the slope of the Lineweaver-Burk plot for acetaldehyde oxidation by ALDH of 0.48 mumol/L. The results of this study suggest that the aldehydic lipid peroxidation product, trans-4-hydroxy-2-nonenal, is a potent inhibitor of hepatic acetaldehyde oxidation and may potentiate the hepatocellular toxicity of acetaldehyde proposed to be an etiological factor of alcoholic liver disease.