Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1332347 (ADH)
 2,230 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic microsomes catalyze the oxidation of ethanol and other drugs. The mechanisms through which ethanol alters mixed function oxidation are still debated. There is evidence that ethanol and drugs interact at a microsomal level, but there are also claims that ethanol may interfere with drug metabolism indirectly by affecting the supply of NADPH through NADH production in the ADH pathway. To investigate the role of chronic ethanol consumption, deermice with normal liver ADH (ADH+) or genetically lacking ADH (ADH-) were pair-fed liquid diets containing ethanol or isocaloric carbohydrate for 23 days. The acute effects of ethanol were studied in deermice fed standard laboratory chow and tap water ad lib. In vivo and in vitro, the effects of an acute dose of ethanol and chronic ethanol feeding on mixed function oxidation as measured by the demethylation of aminopyrine were similar in both animal strains. Statistical analysis showed no significant differences between ADH+ and ADH- animals under all experimental conditions studied. We conclude that induction and inhibition of mixed function oxidation by ethanol may be related to the interaction of ethanol with hepatic microsomes rather than to redox changes produced by ADH mediated ethanol metabolism.
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PMID:Effects of acute ethanol administration and chronic ethanol feeding on mixed function oxidation in deermice lacking ADH. 316 Mar 66

The structure and kinetics of the isozymes from Saccharomyces cerevisiae (ADH I, II, III) have been compared, and the ADH I gene was specifically mutagenized in order to substitute amino acid residues of particular interest. A model of the yeast enzyme was constructed on the basis of the structure of the homologous horse liver enzyme. Steady state kinetic studies, at pH 7.3 and 30 degrees C, showed that the enzymes follow the Ordered Bi Bi mechanism. ADH II has a Michaelis constant for ethanol that is 10-fold smaller than the constants found for ADH I or III. Replacement of Met-294 (liver numbering) in the substrate binding pocket of ADH I with Leu, as found in ADH II, could be responsible for the different kinetics. However, the mutant enzyme, ADH I-Leu, had constants with ethanol that were similar to those of ADH I. Nevertheless, the Leu enzyme had better catalytic activity with longer chain alcohols than did the Met enzyme. Other substitutions must account for the differences between ADH I and II. His-47 binds the pyrophosphate of coenzyme, and replacement with Arg (as in the liver enzyme) decreases turnover numbers by 6-fold and dissociation constants for NAD+ and NADH by only 2 to 4-fold. The lower turnover number explains why yeast harboring the mutant Arg enzyme are resistant to poisoning by allyl alcohol. ADH I and ADH I-Arg have maximal activity on ethanol at pH values above a pK of about 7. Replacement of His-51 with Gln reduces activity 12-fold and abolishes the pK value.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Structure and function in yeast alcohol dehydrogenases. 330 37

The beta 3 beta 3 (formerly called beta Indianapolis) and beta 1 beta 1 isoenzymes of human alcohol dehydrogenase differ substantially in their catalytic properties. Specifically, the KM value for NAD+ of beta 3 beta 3 is 70 times greater than that of beta 1 beta 1, and the Ki value for NADH is 35 times greater than that of beta 1 beta 1. To identify the structural basis of these catalytic differences, we sequenced regions of the beta 3 subunit and the beta 3 gene. beta 3 differs from beta 1 by the substitution of Cys for Arg-369. Based on x-ray crystallography of horse ADH, Arg-369 should interact with the nicotinamide phosphate moiety of NAD(H). The Cys for Arg-369 substitution would decrease the enzyme's affinity for coenzyme and, thus, account for the observed kinetic differences between beta 3 beta 3 and beta 1 beta 1.
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PMID:The human beta 3 alcohol dehydrogenase subunit differs from beta 1 by a Cys for Arg-369 substitution which decreases NAD(H) binding. 361 18

The activity of prostaglandin (PG)E2-9-ketoreductase (9KR), an enzyme catalyzing the conversion of PGE2 to PGF2 alpha, was significantly increased in glomerular and cortical homogenates of diabetes insipidus (DI) rats, as compared to normal Long Evans (LE) rats, and did not change with ADH treatment. Medullary 9KR was similar in the three groups and papillary 9KR was increased, but not significantly, in both groups of DI rats. Km values for PGE2 and NADH were compared in the various compartments of the kidney. Levels of 9KR were not correlated with the PGE/PGF ratio in urine or supernatants. The synthesis of PGE2 and PGF2 alpha by isolated glomeruli was increased in DI rats. This was not reversed by ADH treatment, PGE2 synthesis increasing even further, especially in the presence of arachidonic acid. In contrast, medullary slices produced significantly less PGs in DI than in LE rats and returned to normal with ADH treatment. Papillary slices produced similar quantities of prostaglandins in all groups. The results do not support the concept that the alterations in PG synthesis observed in DI rat are related only to changes in 9KR activity, but do not exclude the possibility that the enzyme participates in the regulation of PG biosynthesis.
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PMID:NADH-dependent prostaglandin E2-9-ketoreductase activity and prostaglandin synthesis in the Brattleboro rat kidney: effects of the antidiuretic hormone. 378 10

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

Alcohol dehydrogenase activity in mouse liver homogenate-supernatants is 1.7 times greater in the C57BL/10 strain than in the BALB/c strain, regardless of whether activity is expressed in units per gram liver, total liver, or milligram DNA. The Km values for ethanol and NAD+, approximately 0.4 and 0.03 mM, respectively, of enzyme purified from both strains are similar. Moreover, the Ki for NADH, 1 microM, the pH optimum for ethanol oxidation, 10.5, and the Vmax for ethanol oxidation, 160 min-1, for ADH from the C57BL/10 and BALB/c strains are similar. Therefore, the difference in ADH activity in the two strains cannot be due to differences in the catalytic properties of the enzyme. The electrophoretic and isoelectric focusing patterns and two-dimensional tryptic peptide maps of the purified enzyme from both strains are identical. Thus the amino acid sequences of enzyme from C57BL/10 and BALB/c mice must also be identical or very similar. The difference in ADH activity in the two strains is most likely the result of genetic differences in the content of ADH protein in liver.
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PMID:Purification and characterization of mouse alcohol dehydrogenase from two inbred strains that differ in total liver enzyme activity. 637 Feb 28

chi-Alcohol dehydrogenase (chi-ADH), a class III isozyme characterized by its anodic electrophoretic mobility and lack of inhibition by 4-methylpyrazole, has been isolated from human liver and purified to homogeneity in a reducing medium. chi-ADH resembles other human liver ADH isozymes of classes I and II with respect to its molecular weight, dimeric structure, stoichiometry of zinc and NADH binding, and pH optima for the oxidation of alcohols. This homodimer exhibits subtle differences in its absorption spectrum and amino acid composition relative to those of other human isozymes but differs markedly from their specificity toward alcohols and aldehydes. chi-ADH oxidizes ethanol very poorly. The reaction is bimolecular, and an apparent Km cannot be discerned up to 2.3 M ethanol. The enzyme is inactive toward methanol, ethylene glycol, digitoxigenin, digoxigenin, and gitoxigenin , but alcohols with carbon chain lengths greater than four are oxidized rapidly with Km values decreasing with increasing carbon chain length. Taken jointly, the composition, structure, and enzymatic properties of the ADH isozymes purified and studied so far strongly imply that their metabolic roles, yet to be discovered, will give a new perspective to ethanol metabolism and pathology.
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PMID:Physical and enzymatic properties of a class III isozyme of human liver alcohol dehydrogenase: chi-ADH. 637 18

Concomitant findings of isopropanol and acetone in biospecimens of decedents known not to have been exposed to the alcohol prompted a study to explain its origins. Mixtures of acetone, ADH, and NADH at pHs 7.3 and 8.8 were incubated at 37 degrees C for varying intervals. Reaction products were then analyzed by headspace GC and assured identification made by GC/MS. It was found that isopropanol is produced by reduction of acetone at pH 7.3 (to a lesser extent at pH 8.8), providing evidence for an alternate metabolic route for acetone. A mechanism for this reduction is proposed. Ranges for isopropanol (in mg/dL or mg/100 g) found in unexposed decedents were: blood 1-29; liver 7-59; brain 2-12; kidney 6-26. Thus, the forensic investigator must interpret isopropanol results cautiously, particularly when low concentrations are found.
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PMID:Endogenous isopropanol: forensic and biochemical implications. 638 78

1. The redox state of mitochondrial NAD was monitored fluorometrically as a function of active ion transport work in the isolated doubly perfused bullfrog kidney. 2. Initial experiments to measure the O2 consumption (QO2) of small pieces from the bullfrog kidney gave a basal QO2 - 3.0 (+/- 0.43) nmoles O2/mg dry wt. min. Addition of 50 microM-ouabain inhibited QO2 by 72.7%. Subsequent addition of the mitochondrial uncoupler 1799 stimulated QO2 by 226%, while cyanide totally inhibited respiration. 3. Ion transport functional parameters and NADH fluorescence were simultaneously monitored during systematic reductions in perfusate PO2 to test the sufficiency of O2 delivery to the isolated perfused frog kidney. No significant changes in transport functions or fluorescence were observed until the PO2 dropped to 184 mm Hg or below. O2 tensions of 184 mm Hg or below caused decreases in G.F.R. and transport functions which were accompanied by an increase in NADH fluorescence. The lack of changes in kidney function in the PO2 range 550-340 mmHg suggested that the tissue is adequately oxygenated at the normal perfusate PO2 of 550 mmHg. 4. The relationship between active transport rate and NAD redox levels was studied by increasing transport work (via increased G.F.R. or ADH) or by decreasing transport work (via decreased G.F.R. or ouabain) while simultaneously monitoring the NAD redox state of the intact tissue fluorometrically. In all cases, an increase in work caused a net oxidation of NAD while a decrease in work caused a reduction of NAD. 5. It is concluded that the NADH fluorescence responses are indicative of mitochondrial active to passive transitions in response to changes in active transport work. The aerobic production of ATP and the normally functioning Na-K-ATPase appear to be essential to maintain active transport and to elicit the appropriate state transitions. Thus, ATP (and, possibly, ADP and Pi) may be part of the coupling mechanism linking active ion transport and aerobic metabolic rate in the kidney.
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PMID:Coupling of aerobic metabolism to active ion transport in the kidney. 696 4

A general survey of the ethanol metabolism and the sequels resulting from this of different kind and intensiveness is given. The speed of the absorption of ethanol is determined according to the laws of diffusion above all by dose and concentration of the ethanol taken. The duration corresponding to the facts varies in broad limits between 10 and 180 min. Nearly simultaneously with the absorption the distribution of the ethanol into the tissues takes place. According to its overwhelming water solubility the ethanol content of the individual tissues is of different size when a distribution balance developed. Three enzyme systems independent of each other, the ADH, the MEOS and the katalase participate in the elimination of the ethanol, the maximum speed of degradation of which lies at the in every case different values of blood alcohol. These three enzyme systems further differ by various localisation, inhibitors, coferments, beginning of activity, optimum of activity and adaptive induction to ethanol. Demarcating for the first step of degradation and thus finally of the ethanol degradation in general might probably be the reoxydation rate, particularly of the NADH, and its repeated inclusion into the ethanol metabolism. Chronic intake of alcohol has multiple effects, among others due to the perhaps temporarily limited adaptive induction of MEOS it has altogether higher rates of degradation. These again have numerous negative sequels with sensitive disturbance of numerous physiologic processes of the intermediary metabolism, in which cases through functional processes finally result organic changes of different kind.
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PMID:[Clinically relevant aspects of ethanol metabolism]. 702 48


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