Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.1.1.1 (alcohol dehydrogenase)
 9,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mice (Mus musculus) from four genetic strains (BALB/c, C57BL/6J, 129/ReJ, and SW) and their F1 hybrids (SWxBALB/c, C57BL/6JxBALB/c, and C57BL/6Jx129/ReJ) were used to evaluate the effect of ethanol on the activity of the two primary enzymes, alcohol dehydrogenase (ADH; E.C.1.1.1.1) and aldehyde dehydrogenase (ALDH; E.C. 1.2.1.3), of alcohol metabolism. Three week-old male mice (12-16 g) were placed on liquid diet (5% ethanol) while a weight-matched littermate control was fed isocaloric maltose-dextrin in place of ethanol. Animals were sacrificed after 3 weeks and the liver and stomach were excised for biochemical analysis. Although the ethanol feeding did not influence the stomach ADH and ALDH activity levels, these enzymes in the liver were affected. The liver ADH activity was depressed to varying degrees in all mouse genotypes studied. Also, the ethanol feeding altered the liver-ALDH activity, which was highly variable and genotype specific. The mice of C57BL/6J and F1 C57BL/6JxBALB/c, both relatively resistant genotypes, exhibited significant increase in liver ALDH-(cytosolic and whole liver homogenate) activity. The response in the other genotypes were not significantly different from their matched controls. The relative resistance of the C57BL/6J strain may be associated with the increase in liver ALDH activity which is expected to facilitate the elimination of acetaldehyde, the toxic metabolite. The results from the selected F1 crosses indicate a multigene system regulating the inducibility of the liver ALDH. The relative sensitivity of different genotypes may be attributed to inducibility components regulating the liver enzyme activity, particularly liver ALDH following challenges with ethanol. These observations may offer a new approach in explaining extensive variability in response to alcohols in most populations.
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PMID:Genetically determined response of hepatic aldehyde dehydrogenase activity to ethanol exposures may be associated with alcohol sensitivity in mouse genotypes. 327 58

1. The activity of liver microsomal high Km-ALDH and mitochondrial low Km-ALDH, which may be primarily responsible for the oxidation of acetaldehyde after ethanol administration was found to be predominantly distributed in the centrilobular area. 2. The activities of other ALDH isozymes in mitochondrial and soluble fractions were evenly distributed in periportal and perivenous regions. 3. The activity of ADH which is involved in production of acetaldehyde was predominantly located in the periportal area. 4. From these results it seems unlikely that a concentration of acetaldehyde after ethanol ingestion is higher in perivenous hepatocytes than in periportal ones. Additional data would be needed to understand fully the mechanism by which ethanol induces predominantly centrilobular liver injury.
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PMID:Intralobular distribution of rat liver aldehyde dehydrogenase and alcohol dehydrogenase. 336 1

The effects of taurine, its initial precursor L-cysteine, and the major metabolite taurocholic acid on two ethanol-mediated responses in rodents were studied. Administration of a single dose of taurocholic acid reduced voluntary intake of a 5% ethanol solution by the rat. In the mouse, taurine had no effect on alcohol drinking or on the central depressant action of ethanol, as measured by the duration of ET-produced loss of the righting reflex. Likewise, taurocholic acid and L-cysteine did not significantly influence the duration of ethanol-narcosis time from control mice. Also studied were the effects of acute and short-term (7 or 10 days) administration of these compounds on hepatic ethanol and acetaldehyde metabolizing enzymes. Short-term administration of an equimolar concentration of taurine enhanced endogenous NADP-linked rat liver aldehyde dehydrogenase (L-ALDH) as contrasted with inhibition of the same enzyme by L-cysteine. Short-term (7 days) treatment with L-cysteine induced rat liver NAD-linked ALDH, but acute (single dose) treatment did not. Taurocholic acid short-term administration caused an induction and an inhibition of endogenous mouse liver alcohol dehydrogenase (L-ADH) and L-ALDH, respectively. The results suggest that taurine does not directly interact with ethanol. However, its major metabolite, taurocholic acid, may cause rapid metabolic conversion of ethanol to acetaldehyde by induction of L-ADH, which is then slowly metabolized due to a concomitant inhibition of L-ALDH. This may cause a build-up of acetaldehyde and thereby produce adverse reactions similar to those resulting from the combination of disulfiram and ethanol.
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PMID:Differential response of NADP-linked hepatic aldehyde dehydrogenase toward taurine: implication for behavioural effects of ethanol. 362 78

The effect of short-term intake of LiCl in drinking water on mouse liver alcohol dehydrogenase (L-ADH) and aldehyde dehydrogenase (L-ALDH) was studied in the albino and in the C57BL mouse strain. The Li-treatment induced initially mitochondrial L-ALDH which was followed by L-ADH in the albino mouse. This was not apparent in the C57 mouse strain. There was an induction of hepatic L-ADH and L-ALDH in the C57BL mouse subsequent to short-term administration of chlorpromazine (CPZ). Coadministration of LiCl with CPZ resulted in moderate enhancement of enzymatic activity per mg wet liver tissue from corresponding controls. Chlorpromazine inhibited rat liver and testicular ADH when tested in vitro. Both cytoplasmic and mitochondrial ALDH were not altered by CPZ in vitro. The results suggest that alcohol consumption during treatment with both drugs studied could evoke metabolic adverse reactions which appear to be both species and strain dependent.
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PMID:Effect of separate and combined treatment with chlorpromazine and lithium on mouse liver alcohol and aldehyde dehydrogenase. 609 69

In vivo and in vitro studies have been presented to suggest an interrelationship between drugs used in the management of, or known for their induction of extrapyramidal disorder and certain dehydrogenase enzymes involved in this metabolic pathway of the biogenic amines. This relationship is discussed to advance a tentative hypothesis explaining a possible underlying mechanism and to provide an explanation for the implication of alcohol consumption in worsening of extrapyramidal symptoms during certain pharmacotherapy. The major neutral metabolites of the biogenic amines acted as substrate to or induced rat liver alcohol dehydrogenase (L-ADH) and drugs used in the management of tardive dyskinesia similarly induced L-ADH. This induction of L-ADH could enhance the metabolic biotransformation of the neutral metabolites of the monoamines. Conversely, drugs known to evoke extrapyramidal dyskinesias inhibited rat liver aldehyde dehydrogenase (L-ALDH). This inhibition of ALDH may give rise to toxic condensation products between biogenic amine aldehydes and their precursors which may be implicated in certain dyskinesias. It is proposed that one of the mechanisms underlying the biogenic amine involvement in the pathogenesis of certain extrapyramidal diseases may include a critical balance between their reductive and oxidative routes of metabolism.
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PMID:Extrapyramidal disorders: a possible underlying mechanism. 613 36

Behavioral, biochemical and histological techniques were used to evaluate the possible interaction between a lithium salt and ethanol. Injection of a single dosage of ethanol into mice pretreated with LiCl for 14 days enhanced spontaneous locomotor activity for the initial 60 min of testing compared to respective control. Drinking of 0.4% of LiCl solution for 25 consecutive days induced hepatic alcohol dehydrogenase (L-ADH) and aldehyde dehydrogenase (L-ALDH). The LiCl treatment increased Vmax of both enzymes in the same order and magnitude. The apparent Km of L-ADH was increased by LiCl while that of L-ALDH remained unchanged from respective controls. Organ histopathology indicates decreased germinal activity of the mouse spleen by the LiCl treatment. A mild chronic perivascular inflammation and slight hypercellularity of the myocardium was also noted in the heart of LiCl-treated mice.
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PMID:Behavioral, metabolic and histological aspects of lithium and ethanol interaction. 631 9

The in vitro effect of propranolol, a beta-receptor blocking agent, on specific activity of hepatic alcohol dehydrogenase (L-ADH) and aldehyde dehydrogenase (L-ALDH) was studied in the male and in the female rat. The presence of propranolol, in the dose range of 3 x 10(-4) M to 10(-3) M concentration in the reaction mixture noncompetitively inhibited female but not male L-ADH. Conversely, significant enhancement of mitochondrial but not cytoplasmic L-ALDH occurred in the presence of propranolol, between 10(-3) M and 10(-5) M concentration, in both sexes. The alteration of hepatic ethanol and acetaldehyde metabolizing enzymes by propranolol suggest both gender difference and possible contraindication of use of this drug in alcoholic patients.
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PMID:Gender and propranolol-ethanol interaction. 634 30

The in vivo and in vitro effect of chlorpromazine (CPZ) on female mouse liver alcohol dehydrogenase (L-ADH) and mitochondrial aldehyde dehydrogenase (L-ALDH) was studied as a function of illumination conditions. Chlorpromazine was injected once daily in a gradual dose build-up from 5 to 30 mg/kg, i.p., over 21 consecutive days. This resulted in a noncompetitive inhibition of endogenous L-ALDH of mice housed under UV light exposure but not those maintained under standard laboratory fluorescent lighting and receiving identical CPZ treatment. No changes occurred in L-ADH in vivo but a noncompetitive inhibition of mouse L-ADH was determined in the presence of 50 muMol of CPZ in vitro. The results are discussed in reference to possible toxic mechanism underlying CPZ and ethanol interaction.
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PMID:Modification of mouse liver alcohol and aldehyde-dehydrogenase by chlorpromazine. 635 84

Acute alcohol intoxication is far more commonly observed in Orientals than Caucasians. The human liver contains several cytosolic and microsomal ADHs. One of the major cytosolic ADH isozymes controlled by a gene at the ADH2 locus differs between Caucasians and Orientals. Most Caucasians have the usual enzyme consisting of usual beta 1 subunit, while nearly 90% of Orientals have the atypical enzyme consisting of the atypical beta 2 subunit. The specific activity of the atypical enzyme is several times higher at pH 10 and nearly 100 times higher at physiologic pH than the usual enzyme. Km values for ethanol, NAD, acetaldehyde, and NADH are several times higher for the atypical enzyme than for the usual enzyme. The usual enzyme is rapidly inactivated by iodoacetate, indicating the existence of an "active-site cysteine" in the molecule. In contrast, the atypical enzyme is resistant to iodoacetate inactivation. Peptide mapping analysis revealed that the active site Cys in the usual beta 1 subunit is replaced by His in the atypical beta 2 subunit. A remarkable structural homology exists at the active site of horse and human enzymes. In the usual beta 1 beta 1 enzyme, as in the horse enzyme, the catalytic Zn is expected to link to the sensitive Cys at position 47, His at position 67, and Cys (presumably) at position 174, thus forming the active site. In contrast, the active site of the atypical beta 2 beta 2 enzyme is expected to consist of the catalytic Zn linked to His at position 47, His at position 67, and Cys (presumably) at position 174. The resistance of the atypical beta 2 beta 2 to inactivation by iodoacetate is a direct consequence of the replacement of the sensitive Cys at position 47 by His. Liver ALDH components also differ between Caucasians and Orientals. Virtually all Caucasians have two major ALDH isozymes, ALDH1 and ALDH2, while approximately 50% of Orientals have only the ALDH1 isozyme (cytosolic) missing ALDH2 isozyme (presumably mitochondrial). ALDH1 consists of four subunits with a molecular weight of 56,500, and ALDH2 consists of four subunits with a molecular weight of 52,600. The two isozymes do not share any common subunit. Examination of liver extracts by two-dimensional crossed immunoelectrophoresis revealed that an atypical Oriental liver with no ALDH2 isozyme contained an enzymatically inactive but immunologically cross-reactive material corresponding to ALDH2, besides the active ALDH1 isozyme.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differences in the isozymes involved in alcohol metabolism between caucasians and orientals. 635 99

The metabolism of acetaldehyde has received considerable attention in the past few years due to its toxic effects and possible importance in pharmacogenetics. Recent studies have demonstrated rapid progress concerning the multiple molecular forms of ADH and ALDH and their genetic variants. The isozymes of ALDH may play an important role in the biological sensitivity to alcohol in certain ethnic groups and also in the pathogenesis of alcohol related organ damage. A protective effect of ALDH I deficiency against alcoholism seems to exist in Japanese.
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PMID:Pharmacogenetics of alcohol sensitivity. 635 57


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