Inhibition Of Liver Alcohol Dehydrogenase Research Articles

Inhibition of alcohol dehydrogenase by disulfiram; possible relation to the disulfiram-ethanol reaction

Disulfiram inhibited mouse and rat liver alcohol dehydrogenase (LADH) in vitro . Inhibition of LADH by disulfiram appears to be non-competitive. The inhibition constants (Ki) were about 1.5 × 10 −4 M and 4.3 × 10 −5 M for mouse and rat LADH respectively. Ethanol elimination was significantly reduced in mice pretreated with disulfiram. At identical time intervals after ethanol administration, the concentration of ethanol in blood from disulfiram-, cyanamide-, or dimethyl formamide-treated mice were significantly higher than the ethanol concentration in blood from control mice. Both cyanamide and dimethyl formamide (DMF) can precipitate a disulfiram-like reaction in man when ethanol is ingested. These and previous experiments suggest that elevated concentrations of ethanol should be considered in the etiology of some of the symptoms seen in the disulfiram-ethanol reaction.

Isoniazid‐induced intolerance to ethanol in rabbit, guinea pig and rat

AbstractIsoniazid (50 or 100 mg kg−l p.o.) inhibited the elimination of ethanol (0·5, 1·0, and 2·5 g kg−l p.o.) from the plasma of rabbit, guinea pig, and rat. The effect of isoniazid, isonicotinic acid, N‐acetylisoniazid, N‐acetylhydrazine, N,N‐diacetylhydrazine, and hydrazine on the in vitro metabolism of alcohol by rabbit liver alcohol dehydrogenase was examined. Only isoniazid, hydrazine, and acetylisoniazid showed significant inhibitory activity with I50's of 17·7, 1·25, and 0·78 mmol 1−1 respectively. Intolerance to ethanol following isoniazid treatment was attributed to isoniazid inhibition of liver alcohol dehydrogenase.

Multifunctionality of liver alcohol dehydrogenase. Studies of aldehyde dehydrogenase activity

Kinetic studies of the liver alcohol dehydrogenase catalyzed dehydrogenation of aldehydes were carried out over a wide range of octanal concentrations. The effect of specific inhibitors of liver alcohol dehydrogenase on aldehyde dehydrogenase activity was examined. The results were consistent with a steady-state random mechanism with the formation of the ternary E · NADH octanal complex at low temperatures. This ternary complex becomes inconspicuous at high temperatures. The aldehyde dehydrogenase activity was found to associate with all ethanol-active isozymes. The dual dehydrogenase reactions are catalyzed by the same molecule, presumably in the region of the same domain. However, the two activities respond differently to structural changes.

Exo-Bicyclo[4.1.0]heptane-7-methanol: a novel latent inhibitor of liver alcohol dehydrogenase

Oxidation of exo-bicyclo[4.1.0]heptane-7-methanol by horse liver alcohol dehydrogenase and NAD+ leads to the irreversible inactivation of the enzyme and in the presence of NADH, the enzyme catalyses the slow solvolytic ring-opening of the substrate.

Cyclobenzaprine and ethanol interaction

The effects of cyclobenzaprine, a tricyclic compound, on the central depressant action of ethanol and on hepatic ethanol metabolizing enzymes were studied in rodents. Administration of cyclobenzaprine, 5 mg/kg, IP, 30 min prior to a narcotic dose of ethanol solution, 5 g/kg, IP, enhanced ethanol-produced narcosis in mice. This effect was greater in male than in female mice. Cyclobenzaprine inhibited endogenous rat liver alcohol dehydrogenase in vitro in the concentration range between 10 −5M and 10 −6M. Cyclobenzaprine exerted little effect on hepatic aldehyde dehydrogenase in vitro. The results suggest that cyclobenzaprine possesses depressant properties and inhibition of liver alcohol dehydrogenase may underlie the observed behavioral response studied. It is concluded that alteration of endogenous liver alcohol dehydrogenase by certain tricyclic antidepressant drugs may be involved in the mechanism(s) of their toxic interaction with ethanol.

Latent inhibition of liver alcohol dehydrogenase by a substituted allyl alcohol

3-Ethylthioprop-2-en-1-ol is a substrate for liver alcohol dehydrogenase and also causes time-dependent inactivation of the enzyme.

Epoxide inhibition of alcohol dehydrogenases. Identification of modified cysteines in yeast alcohol dehydrogenase and demonstration of reversible and irreversible inhibition of liver alcohol dehydrogenase by styrene oxide

Epoxide inhibition of alcohol dehydrogenases. Identification of modified cysteines in yeast alcohol dehydrogenase and demonstration of reversible and irreversible inhibition of liver alcohol dehydrogenase by styrene oxide

Ethanol preference in the rat following inhibition of liver alcohol dehydrogenase and S-adenosyl methionine.

AbstractA preference for alcohol was established in laboratory rats offered a choice of water or an alcohol solution and kept in constant darkness. They were administered pyrazole, an inhibitor of liver alcohol dehydrogenase (LADH) or homocysteine or homoserine, inhibitors of S‐adenosyl methionine (SAM). These agents reduced alcohol intake in varying degrees. Similarly, a reduction of alcohol drinking occurred following simultaneous administration of ineffective doses of pyrazole with homocysteine or homoserine.

Studies on the ethanol-induced decrease of fatty acid oxidation in rat and human liver slices

In order to elucidate the mechanisms involved in the acute ethanol-induced liver triglyceride accumulation, the oxidation, esterification and β-keto acid formation have been studied in rat and human liver slices after incubation with albumin bound, long chain fatty acids (palmitic. oleic and linoleic acids). The addition of alcohol to rat and human liver slices depressed the formation of 14CO 2 from palmitic acid-1- 14C, oleic acid-1- 14C and linoleic acid-1- 14C. The esterification to triglycerides and phospholipids was increased and the formation of β-keto acids was decreased by alcohol. Addition of 4-methylpyrazole, an inhibitor of liver alcohol dehydrogenase, almost prevented the alcohol effect on the lipid metabolism of the liver slices. The oxidation of alcohol is thus obligatory for the decreased β-oxidation of fatty acids, the increased esterification and for the decreased formation of β-keto acids. The results suggest that ethanol oxidation inhibits β-oxidation of fatty acids and that this primary effect leads to accumulation of liver triglycerides by increased esterification of plasma free fatty acids.

Time course of the acute alcoholic fatty liver and concomitant mitochondrial function in fasted rats.

SummaryPyrazole, an inhibitor of liver alcohol dehydrogenase and ethanol metabolism, was used to distinguish between acute biochemical responses produced directly by alcohol and secondarily by its metabolic effects. Over the 40 hr period studied, accumulation of hepatic triglvcerides was dependent upon an initial uptake of fattv acids from adipose stores and continued oxidation of ethanol by the liver. The increased efficiency of mitochondrial function, as monitored by the magnitude of respiratory control ratios, followed a time course isochronous with the blood alcohol curve and was dependent upon in situ exposure of the organelle to the alcohol molecule, not its metabolic seauelae. These relatively short-term responses are not sustained in well nourished animals receiving ethanol chronically.The technical assistance of Mrs. Regina Foster is gratefully acknowledged.

The Site of Auramine O Binding to Horse Liver Alcohol Dehydrogenase

Abstract In agreement with an earlier report (Conrad, R. H., Heitz, J. R., and Brand, L., Biochemistry, 9, 1540 (1970)), auramine O was found to bind to horse liver alcohol dehydrogenase at two equivalent noninteracting sites per enzyme molecule, with an intrinsic dissociation constant Kr = 1.65 x 10-5 m in 0.05 m phosphate buffer at pH 7.0 at 25°. The dye was displaced competitively from the enzyme by substrates (ethanol and 1-butanol), substrate inhibitors (decanoic acid, imidazole, and pyrazole), and by inhibitors binding to the zinc ion presumed to be at the active site (1,10-phenanthroline and 2,2-bipyridine). The dye forms ternary complexes, with comparable affinity, with the binary complexes of the enzyme with NAD+, NADH, and adenosine diphosphoribose. In all three cases, the dissociation constant of auramine O from the ternary complex is significantly lower than the dissociation constant for the enzyme-auramine O binary complex. On the basis of the noncompetitive inhibition of liver alcohol dehydrogenase by auramine O in initial rate studies, Conrad et al. suggested that the dye binding site is distinct from the coenzyme and substrate binding sites. This interpretation is incompatible with the data summarized above. The apparent noncompetitive inhibition kinetic data are shown here to be the consequence of the unique ability of the dye to form ternary complexes with the enzyme-NAD+ and enzyme-NADH binary complexes. Thus, the auramine O-alcohol dehydrogenase interaction offers an additional case to the general correlation that most dyes which bind tightly to enzymes interact at regions overlapping binding sites for the normal ligands.

Inhibition of liver alcohol dehydrogenase by primaquine and 8-amino-6-methoxyquinoline compounds

The effect of primaquine, chloroquine and other aminoquinoline derivatives on the enzymatic activity of crystalline horse liver alcohol dehydrogenase and partially purified human liver alcohol dehydrogenase has been studied. While chloroquine inhibits neither enzyme, primaquine inhibits both the horse and the human enzyme reversibly and noncompetitively with respect to NAD. The inhibition constant is 2 μM for the horse enzyme and 30 μM for the human enzyme. Spectrophotometric studies of the interaction of primaquine with the horse liver enzyme indicate that primaquine binds to a specific hydrophobic site on the protein. The stoichiometry of binding measured by spectrophotometric titrations is 2 moles primaquine/mole of enzyme and the dissociation constant of the complex is 3 μM. The effects of other 8-amino-6-methoxyquinoline compounds upon horse and human liver alcohol dehydrogenases suggest that the aliphatic side chain, as well as the terminal primary amino group of the side chain, contributes importantly to the tight binding of primaquine to these enzymes.

Studies on liver alcohol dehydrogenase complexes: III. Multiple inhibition kinetics in the presence of two competitive inhibitors

A graphical method was devised to analyze the multiple inhibition of an enzyme by two competitive inhibitors. This method not only distinguishes whether two inhibitors interact with the same site or different sites of the enzyme, but also gives an interaction constant (α) between two inhibitors in the enzyme-inhibitor complex. This method was applied to the multiple inhibition of liver alcohol dehydrogenase by coenzyme-competitive inhibitor pairs among o-phenanthroline, adenosine diphosphate ribose, and adenosine-5′-mono- and -diphosphates. The present kinetic analysis quantitatively reconfirmed our previous conclusion that o-phenanthroline and adenosine diphosphate ribose interact independently with different sites of the enzyme.

ANOMALOUS ROTATORY DISPERSION OF ENZYME COMPLEXES.IV. MECHANISM OF INHIBITION OF LIVER ALCOHOL DEHYDROGENASE BY BUFFER ANIONS AND BASES.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAnomalous Rotatory Dispersion of Enzyme Complexes. IV. Mechanism of Inhibition of Liver Alcohol Dehydrogenase by Buffer Anions and Bases*Ting-Kai Li, David D. Ulmer, and Bert L. ValleeCite this: Biochemistry 1963, 2, 3, 482–486Publication Date (Print):May 1, 1963Publication History Published online1 May 2002Published inissue 1 May 1963https://doi.org/10.1021/bi00903a015RIGHTS & PERMISSIONSArticle Views40Altmetric-Citations24LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (611 KB) Get e-Alerts Get e-Alerts

An Inhibitor of Liver Alcohol Dehydrogenase in Preparations of Reduced Diphosphopyridine Nucleotide

Different samples of reduced diphosphopyridine nucleotide (β-DPNH, Sigma Chemical Co.) have been found to give significantly different maximum rates of reduction of aldehyde catalysed by liver alcohol dehydrogenase. The crystalline enzyme was prepared from horse liver1 and measurements of initial rates were made with a recording fluorimeter1,2 at 23.5°. In Table 1 relative values of initial rates with 1.3 × 10−3 M acetaldehyde and 2 × 10−5 M DPNH in pH 6 phosphate buffer (ionic strength 0.1) are collated with assays of the samples of DPNH. The percentage by weight of anhydrous disodium salt was calculated from direct extinction measurements at 340 mµ (column 2), and also from the decrease of absorption of light at this wave-length (ΔE340) accompanying complete oxidation of the coenzyme by excess acetaldehyde and liver alcohol dehydrogenase (column 3), using in each case the value 6.22 (ref. 3) for the millimolar extinction coefficient. The second value is taken to be the true DPNH content. The difference between the two values is due to the presence of a substance which closely resembles DPNH in both light absorption and fluorescence emission, but is not coenzymically active with liver (or yeast) alcohol dehydrogenase. The results indicate that the samples which give the higher initial rates have the greater coenzyme content and a smaller excess of total adenine over coenzyme (column 4). Ribose and total phosphate analyses were also made ; calculating the total adenine content from the extinction at 260 mµ (pH 7) and a millimolar extinction of 15 (ref. 4), the molar ratios of ribose and phosphate to adenine were 2.1 ± 0.1 for all the samples.

Inhibition of Liver Alcohol Dehydrogenase by Amides.

Inhibition of Liver Alcohol Dehydrogenase by Amides.