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)

By using cell-free preparations of rat liver it was shown that the removal of the 14alpha-methyl group (C-32) of steroids containing either a delta7(8) or a delta8(9) double bond is attended exclusively by the formation of the corresponding 7,14- and 8,14-dienes respectively (structures of types III and VIII). Cumulative evidence from a variety of experimental approaches had led to the deduction that delta8(14)-steroids are not involved as intermediates on the major pathway of cholesterol biosynthesis. The metabolism of [32-3H]lanost-7-ene-3beta,32-diol (structure of type I) results in the formation of radioactive formic acid, no labelled formaldehyde being formed. By using appropriately labelled species of the compound (I) it was found that the release of formic acid and the formation of 4,4-dimethylcholesta-7,14-dien-3beta-ol (strurcture of type III) were closely linked processes, and that in the conversion of compound (I) into compound (III), 3-beta-hydroxylanost-7-en-32-al (II) is an obligatory intermediate. Both the conversion of lanost-7-ene-3beta,32-diol (I) into 3beta-hydroxylanost-7-en-32-al (II) and the further metabolism of the latter (II) to 4,4-dimethylcholesta-7,14-dien-3beta-ol (III) exhibited a requirement for NADPH and O2. This suggests that the oxidation of the 32-hydroxy group of compound (I) to the aldehyde group of compound (II) does not occur by the conventional alcohol dehydrogenase type of reaction, but may proceed by a novel mechanism involving the intermediacy of a gem-diol. A detailed overall pathway for the 14alpha-demethylation in cholesterol biosynthesis is considered, and proposals about the mechanism of individual steps in the pathway are made.
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PMID:Chemical and enzymic studies on the characterization of intermediates during the removal of the 14alpha-methyl group in cholesterol biosynthesis. The use of 32-functionalized lanostane derivatives. 2 46

4-Methylpyrazole, in a dose producing inhibition of alcohol dehydrogenase (alcohol:NAD(+) oxidoreductase, EC 1.1.1.1), was given alone or together with ethanol (10%) as sole drinking fluid to growing rats for up to 38 weeks. Their weight curves remained normal. Electron microscopy of liver, kidney, and heart revealed no changes related to treatment. Hematologic analysis showed normal values for blood and bone marrow. Several clinical chemical parameters showed no impairment of liver or kidney function, except for an enhancement of the microsomal drug-metabolizing activity after concurrent administration of 4-methylpyrazole and ethanol. A study on rats receiving 4-methylpyrazole and ethanol indicated a mutual interaction of the two compounds or the metabolites, leading to increased concentration in the blood of the compounds and reduced formation of 4-hydroxymethylpyrazole, the primary metabolite of 4-methylpyrazole. In monkeys, elimination of 4-methylpyrazole followed a linear course. 4-Hydroxymethylpyrazole accumulated to a level of at most 10% of that of 4-methylpyrazole. Concurrent administration of methanol inhibited the elimination of 4-methylpyrazole about 25%, and 4-methylpyrazole produced a profound inhibition of the oxidation of methanol. 4-Methylpyrazole, at a level in the plasma of more than 10 muM, prevented accumulation of the toxic metabolite formic acid in methanol-poisoned monkeys, and repeated injections of 4-methylpyrazole abolished methanol toxicity in monkeys receiving lethal doses of methanol. The present investigation indicates that 4-methylpyrazole, with its low toxicity and strong inhibition of alcohol oxidation, is a valuable tool for experimental studies of alcohol metabolism and its effects. It illustrates the usefulness of the monkey as a model to study 4-methylpyrazole activity and toxicity in light of its possible use for treating methanol poisoning in human beings.
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PMID:Pyrazoles as inhibitors of alcohol oxidation and as important tools in alcohol research: an approach to therapy against methanol poisoning. 11 4

This paper reports the elimination half-life of methanol in human volunteers. Experiments were made during the morning after the subjects had consumed 1000-1500 ml red wine (9.5% w/v ethanol, 100 mg/l methanol) the previous evening. The washout of methanol from the body coincided with the onset of hangover. The concentrations of ethanol and methanol in blood were determined indirectly by analysis of end-expired alveolar air. In the morning when blood-ethanol dropped below the Km of liver alcohol dehydrogenase (ADH) of about 100 mg/l (2.2 mM), the disappearance half-life of ethanol was 21, 22, 18 and 15 min. in 4 test subjects respectively. The corresponding elimination half-lives of methanol were 213, 110, 133 and 142 min. in these same individuals. The experimental design outlined in this paper can be used to obtain useful data on elimination kinetics of methanol in human volunteers without undue ethical limitations. Circumstantial evidence is presented to link methanol or its toxic metabolic products, formaldehyde and formic acid, with the pathogenesis of hangover.
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PMID:Elimination half-life of methanol during hangover. 358 16

Starting from (13C)formic acid, acetone and cyanoacetamide samples of (4-13C)nicotinic acid and (4-13C)-nicotinamide were synthesised in an overall and additive yield of 11%. 1H-NMR and mass spectroscopy showed 90% enrichment of 13C in the expected position. NADase-catalysed exchange between thionicotinamide-adenine dinucleotide and (4-13C)nicotinamide furnished (4-13C)NAD+ which was purified, characterized and quantified by 1H-NMR and 13C-NMR spectroscopy and by enzymic assay. The 13C-NMR signal of (4-13C)beta-NAD+ (146.09 ppm) was broadened and shifted (147.83 ppm) upon binding to yeast alcohol dehydrogenase.
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PMID:Synthesis and properties of (4-13C)NAD+. Observation of its binding to yeast alcohol dehydrogenase by 13C-NMR spectroscopy. 623 Nov 82

Chronic ethanol use can lead to folic acid deficiency in humans. In rats, acute doses of ethanol produce a marked increase in the urinary excretion of folate which is followed by a decrease in plasma folate levels. To assess the respective roles of ethanol and its metabolism in these effects, five groups of male Sprague-Dawley rats were treated orally as follows: (1) ethanol in four doses of 1 g/kg each at 0, 1, 2 and 3 hr; (2) ethanol as above plus the alcohol dehydrogenase inhibitor 4-methylpyrazole (4-MP) at 50 mg/kg, i.p., 15 min prior to 0 hr; (3) glucose in four isocaloric doses; (4) glucose plus 4-MP as above; and (5) methanol in four doses of 1 g/kg. Total folate levels in the urine peaked in both ethanol- and methanol-treated rats at the same time as the urine alcohol levels (after 6-8 hr) and then declined over the same time course as the alcohol levels. Concurrent administration of 4-MP inhibited the metabolism of ethanol and maintained the increase in urinary folate excretion throughout 24 hr. Ethanol administration produced minor changes in the relative distribution of folate derivatives in the urine, and these changes were not prevented by 4-MP treatment. The urinary levels of formic acid, which is metabolized by folate-dependent processes, were increased by ethanol administration; this increase was prevented by 4-MP. These results suggest that ethanol is not unique among alcohols in increasing urinary folate excretion and that ethanol metabolism plays no role in the increased urinary folate excretion. However, ethanol metabolism contributes to a second effect of ethanol on the folate system, which leads to increased urinary levels of formic acid.
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PMID:Role of ethanol metabolism in the alcohol-induced increase in urinary folate excretion in rats. 661 50

Chronic ethanol use can lead to folic acid deficiency in humans. In rats, acute doses of ethanol produce a marked increase in urinary folate excretion, which precedes a decrease in plasma folate levels. To assess the role of ethanol and its metabolism in these effects, five groups of male Sprague-Dawley rats were treated orally as follows: (1) ethanol in 4 doses of 1 g/kg each at 0, 1, 2 and 3 hr; (2) ethanol, as above, plus the alcohol dehydrogenase inhibitor 4-methylpyrazole (4-MP) at 50 mg/kg IP 15 min prior to 0 hr; (3) glucose in 4 isocaloric doses; (4) glucose plus 4-MP as above; (5) methanol in 4 doses of 1 g/kg. Urinary folate levels (by Lactobacillus casei assay) peaked in both ethanol- and methanol-treated rats at the same time as the urine alcohol levels (6-8 hr) and then declined with a similar time course. Urinary levels of formic acid, which is eliminated by oxidation by a folate-dependent pathway, were significantly increased by ethanol administration, thus indicating another ethanol-folate interaction. Concurrent administration of 4-MP suppressed the increased excretion of formate but had no effect on the increased excretion of folate in ethanol-treated rats. These studies suggest that ethanol has two distinct effects on folate metabolism, one dependent and one independent of ethanol metabolism.
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PMID:Relationship of alcohol metabolism to folate deficiency produced by ethanol in the rat. 663 38

Intoxication by methanol was identified in a five-week-old infant suffering from moderate metabolic acidosis. The initial serum methanol at admission was 1148 mg/dL as measured by gas chromatography. The osmolal gap and formic acid concentrations were consistent with methanol intoxication. The child was treated with folic acid and a continuous ethanol infusion and survived without any apparent permanent problems. Because expected toxic symptoms did not develop in this case, and the methanol concentrations were at levels that might be deemed to be incompatible with life, blood and urine samples were assayed by a specific enzymatic assay, and by gas chromatography/mass spectrometry (GC/MS). Positive results definitively confirmed the presence of methanol. In contrast to previous reports, the elimination of methanol in this case appeared to following first-order kinetics. If hepatic ADH activity is low in neonates and young infants, another enzyme system such as catalase may be involved to explain this data. The lack of formic acid accumulation may have been due to folic acid therapy.
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PMID:Definitive identification of an exceptionally high methanol concentration in an intoxication of a surviving infant: methanol metabolism by first-order elimination kinetics. 760 99

The gene (fdm) coding for formaldehyde dismutase (EC 1.2.99.4) from a genomic library of formaldehyde-tolerant Pseudomonas putida F61 was cloned and expressed in Escherichia coli. The nucleotides of the cloned DNA were sequenced; they included a single open reading frame of 1200 base pairs, coding for a putative protein with a molecular weight of 42,848. Sequencing of the first 20 N-terminal amino acid residues and of an internal part of the enzyme purified from P. putida F61 established the identity and the start codon of fdm. Comparison of the amino acid sequence predicted from fdm with that of alcohol dehydrogenase from horse liver suggested a putative pyridine-dinucleotide-binding domain in fdm, and also potential ligands for the catalytic domain and the second zinc atom-folding domain. fdm seemed to be expressed in E. coli under control of the promoter of fdm; there was an E. coli promoter-like sequence upstream from the gene. The enzyme expressed in E. coli was purified to homogeneity. The molecular weight and the sequence of the first 20 N-terminal amino acid residues were identical with those of P. putida formaldehyde dismutase. Each subunit contained 1 mol of NAD(H) and 2 mol of zinc per mol of protein. The enzyme produced in E. coli catalyzed the dismutation of formaldehyde to form methanol and formic acid at the ratio of 1:1 in the absence of the exogenous electron acceptor, NAD(H).
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PMID:Cloning, sequence analysis, and expression of the gene encoding formaldehyde dismutase from Pseudomonas putida F61. 776 17

Fatalities are still reported following methanol poisoning. Methanol is extensively metabolized by alcohol dehydrogenase to formaldehyde and by aldehyde dehydrogenase to formic acid which is the main toxic metabolite. Survival with extremely high blood methanol concentration is possible provided that aggressive symptomatic and specific therapy is applied. This is illustrated by the clinical observation of a 27-year-old man who was admitted 22 hours after poisoning and presented a peak blood methanol concentration of 12.9 g/l. Treatment included correction of metabolic acidosis, ethanol infusion, haemodialysis and peritoneal dialysis. The patient survived with moderate visual sequelae and oesophageal stenosis. The range of toxicity of methanol according to blood levels determination is discussed.
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PMID:Survival with extremely high blood methanol concentration. 1114 77

The appropriate treatment of a patient with methanol intoxication includes the use of a competitive inhibitor of alcohol dehydrogenase (ethanol, p.o. or i.v., or fomepizole) to prevent the metabolism of methanol to formaldehyde and formic acid. Where available, dialysis can be added to this therapy, since methanol is cleared well by hemodialysis. The ability to predict the time course of methanol elimination in any given patient is an essential factor in planning his or her care. Where the availability of ethanol, bicarbonate, nursing time, or dialysis machines is limited, such predictions can be used to allocate these resources quite accurately within a couple of hours of starting treatment. Even when direct measurement of methanol by gas chromatography is not readily available, its level can be estimated indirectly by a quick and easy method, using available laboratory values. The length of time necessary to clear the methanol below a toxic level can be predicted accurately. Careful interpretation of laboratory values can result in early treatment, correct treatment time, and a positive patient outcome.
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PMID:Predicting methanol clearance during hemodialysis when direct measurement is not available. 1197 51


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