Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.1.1.1 (alcohol dehydrogenase)
9,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, it was demonstrated that 4-methylpyrazole was not only an inhibitor of alcohol dehydrogenase but also caused competitive inhibition of fatty acyl-CoA synthetase, the enzyme which activates fatty acids (B. U. Bradford, D. T. Forman, and R. G. Thurman, 1993, Mol. Pharmacol. 43, 115-119). Rates of catalase-dependent alcohol metabolism were decreased in alcohol dehydrogenase-negative (ADH-) deer mice because the H2O2 supply for catalase via peroxisomal fatty acid oxidation was inhibited due to substrate limitation. In light of these findings it became necessary to reevaluate the role of catalase and alcohol dehydrogenase in alcohol metabolism. In this study, methanol, a selective substrate for catalase in rodents, was compared with ethanol. Rates of ethanol and methanol metabolism were studied in vivo at blood alcohol levels ranging from 50 to 500 mg/dl. In the ADH- deer mouse, rates of methanol and ethanol metabolism increased when alcohol was elevated from 0 to 100 mg/dl and were maximal at values around 6-8 mmol/kg/h (half-maximal rates were observed at blood alcohol levels around 50 mg/dl). In the ADH+ deer mouse, rates of ethanol metabolism increased to values around 9 mmol/kg/h at 100 mg/dl and remained constant at blood levels up to 500 mg/dl. In contrast, rates of methanol metabolism increased to values of only 5 mmol/kg/h at levels of 100 mg/dl (the half-maximal rate was about 2.5 mmol/kg/h at 50 mg/dl) followed by a steady increase to 9 mmol/kg/h as the blood level was increased from 100 to 500 mg/dl (the half-maximal rate for this second component was around 6 mmol/kg/h at 300 mg/dl). Rates of methanol uptake were 50 +/- 4 nmol/min/mg protein in 10,000g pellets from ADH- deer mouse livers; however, methanol was not metabolized by isolated microsomes. The catalase inhibitor aminotriazole decreased ethanol and methanol metabolism 75% in ADH- deer mice. Further, olive oil, which is rich in oleate, increased methanol metabolism from 7 to 11.5 mmol/kg/h. This stimulation was blocked by fructose, which diminishes ATP and decreases H2O2 supply. In the ADH+ deer mouse, fructose (2 g/kg) stimulated ethanol metabolism as expected; however, inhibition of both ethanol and methanol metabolism was observed with higher doses of fructose (10 g/kg). Taken together, these data support the hypothesis that catalase is the predominant pathway for alcohol metabolism in the ADH- deer mouse. The contribution of catalase was about 50% in the ADH+ mutant at low doses of ethanol and approached 100% as the alcohol concentration was elevated.
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PMID:Evidence that catalase is a major pathway of ethanol oxidation in vivo: dose-response studies in deer mice using methanol as a selective substrate. 848 62

Ethanol can be oxidized to the 1-hydroxyethyl radical (HER) by rat and deer mice liver microsomal systems. Experiments were carried out to evaluate the ability of human liver microsomes to catalyze this reaction, compare the effectiveness of NADH with that of NADPH, and assess the possible role of cytochrome b5 in HER formation. HER was detected as the alpha-(4-pyridly-1 -oxide)-N-t-butylnitrone/HER adduct. Human liver microsomes catalyzed HER formation with either NADPH or NADH as cofactor; rates with NADH were approximately 50% those found with NADPH. Chelex-100 treatment of the reaction mixture produced marked inhibition of HER formation, suggesting that a transition metal, such as iron, was required to catalyze the reaction. The addition of ferric chloride restore HER formation. Catalase (2600 units/ml) and superoxide dismutases (500 units/ml) nearly completely inhibited the reaction with either NADPH or NADH. The NADH-dependent rates of superoxide production, detected as 5,5-dimethyl-1-pyrroline-N-oxide-O2H, were approximately 50% the NADPH-dependent rates, which is consistent with the rates of HER formation. Anti-cytochrome b5 IgG decreased NADPH- and NADH-dependent HER formation, and this was associated with inhibition of superoxide formation with both reductants. These results indicate that human liver microsomes can catalyze the oxidation of ethanol of HER with either NADPH or NADH as reductant. The effectiveness of NADH may be significant in view of the increased NADH/NAD+ redox ratio in the liver as a consequence of ethanol oxidation by alcohol dehydrogenase. HER formation by human liver microsomes seems to be catalyzed by an oxidant derived from the interaction of iron with superoxide or H2O2, and a close association exists between HER formation and superoxide production. Cytochrome b5 seems to play a role in HER formation, most likely due to its effect on superoxide production.
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PMID:1-Hydroxyethyl radical formation during NADPH- and NADH-dependent oxidation of ethanol by human liver microsomes. 862 31

To evaluate the possible role of catalase in gastric ethanol metabolism in rats, we studied acetaldehyde formation from ethanol by gastric mucosal homogenate under various in vitro conditions. Homogenized rat gastric mucosa produced significant amounts of acetaldehyde in a time and ethanol concentration-dependent manner, even in the absence of added NAD. Both acetaldehyde formation and catalase activity peaked around the physiological pH, whereas alcohol dehydrogenase (ADH) activity was in that pH range low and reached peak values only at a higher pH of 9 to 10. Catalase inhibitors sodium azide (SA) and 3-amino-1,2,4-triazole (3-AT) had little effect on ADH activity but markedly decreased catalase activity and acetaldehyde formation (1 mM of SA to 56 +/- 13% of control, 5 mM of 3-AT to 67 +/- 3% of control; mean +/- SE). 4-Methylpyrazole decreased ADH activity significantly, but did not affect acetaldehyde formation. Heating of the homogenate at 60 degrees C for 5 min decreased ADH activity only slightly, but totally abolished catalase activity and reduced acetaldehyde formation to 39 +/- 3% of control. Addition of a H2O2 generating system (beta-D(+)-glucose + glucose oxidase] increased acetaldehyde formation in a concentration-dependent manner up to 8-fold of the control value. Our results strongly suggest that, in addition to ADH, catalase may play a significant role in gastric ethanol metabolism in rats.
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PMID:Role of catalase in rat gastric mucosal ethanol metabolism in vitro. 889 20

The main pathway for the hepatic oxidation of ethanol to acetaldehyde proceeds via ADH and is associated with the reduction of NAD to NADH; the latter produces a striking redox change with various associated metabolic disorders. NADH also inhibits xanthine dehydrogenase activity, resulting in a shift of purine oxidation to xanthine oxidase, thereby promoting the generation of oxygen-free radical species. NADH also supports microsomal oxidations, including that of ethanol, in part via transhydrogenation to NADPH. In addition to the classic alcohol dehydrogenase pathway, ethanol can also be reduced by an accessory but inducible microsomal ethanoloxidizing system. This induction is associated with proliferation of the endoplasmic reticulum, both in experimental animals and in humans, and is accompanied by increased oxidation of NADPH with resulting H2O2 generation. There is also a concomitant 4- to 10-fold induction of cytochrome P4502E1 (2E1) both in rats and in humans, with hepatic perivenular preponderance. This 2E1 induction contributes to the well-known lipid peroxidation associated with alcoholic liver injury, as demonstrated by increased rates of superoxide radical production and lipid peroxidation correlating with the amount of 2E1 in liver microsomal preparations and the inhibition of lipid peroxidation in liver microsomes by antibodies against 2E1 in control and ethanol-fed rats. Indeed, 2E1 is rather "leaky" and its operation results in a significant release of free radicals. In addition, induction of this microsomal system results in enhanced acetaldehyde production, which in turn impairs defense systems against oxidative stress. For instance, it decreases GSH by various mechanisms, including binding to cysteine or by provoking its leakage out of the mitochondria and of the cell. Hepatic GSH depletion after chronic alcohol consumption was shown both in experimental animals and in humans. Alcohol-induced increased GSH turnover was demonstrated indirectly by a rise in alpha-amino-n-butyric acid in rats and baboons and in volunteers given alcohol. The ultimate precursor of cysteine (one of the three amino acids of GSH) is methionine. Methionine, however, must be first activated to S-adenosylmethionine by an enzyme which is depressed by alcoholic liver disease. This block can be bypassed by SAMe administration which restores hepatic SAMe levels and attenuates parameters of ethanol-induced liver injury significantly such as the increase in circulating transaminases, mitochondrial lesions, and leakage of mitochondrial enzymes (e.g., glutamic dehydrogenase) into the bloodstream. SAMe also contributes to the methylation of phosphatidylethanolamine to phosphatidylcholine. The methyltransferase involved is strikingly depressed by alcohol consumption, but this can be corrected, and hepatic phosphatidylcholine levels restored, by the administration of a mixture of polyunsaturated phospholipids (polyenylphosphatidylcholine). In addition, PPC provided total protection against alcohol-induced septal fibrosis and cirrhosis in the baboon and it abolished an associated twofold rise in hepatic F2-isoprostanes, a product of lipid peroxidation. A similar effect was observed in rats given CCl4. Thus, PPC prevented CCl4- and alcohol-induced lipid peroxidation in rats and baboons, respectively, while it attenuated the associated liver injury. Similar studies are ongoing in humans.
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PMID:Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases. 889 26

Allicin (thio-2-propene-1-sulfinic acid S-allyl ester) is the main biologically active component of garlic clove extracts. Its biological activity was attributed to either antioxidant activity or thiol disulfide exchange. Antioxidant properties of both allicin and its precursor, alliin (+S-allyl-L-cysteine sulfoxide), were investigated in the Fenton oxygen-radical generating system [H2O2-Fe(II)]. Using the spin trapping technique and ESR, it was found that both compounds possessed significant antioxidant activity. The reaction between allicin and L-cysteine was studied by 1H and 13C-NMR, and a S-thiolation product, S-allylmercaptocysteine, was identified. Allicin irreversibly inhibited SH-protease papain, NADP(+)-dependent alcohol dehydrogenase from Thermoanaerobium brockii (TBAD), and the NAD(+)-dependent alcohol dehydrogenase from horse liver (HLAD). All the three enzymes could be reactivated with thiol containing compounds. Papain could be reactivated with glutathione, TBAD with dithiothreitol or 2-mercaptoethanol (2-ME) but not by glutathione, while HLAD could be reactivated only with 2-ME. This study demonstrates that in addition to its antioxidant activity, the major biological effect of allicin should be attributed to its rapid reaction with thiol containing proteins.
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PMID:The mode of action of allicin: trapping of radicals and interaction with thiol containing proteins. 952 59

Many new lines of evidence implicate both superoxide anion radical (O2*-) and biogenic amine neurotransmitters in the pathological mechanisms that underlie neuronal damage caused by methamphetamine (MA), glutamate-mediated oxidative toxicity, ischemia-reperfusion, and other neurodegenerative brain disorders. In this investigation the oxidation of 5-hydroxytryptamine (5-HT, serotonin) by an O2*--generating system (xanthine/xanthine oxidase) in buffered aqueous solution at pH 7.4 has been studied. The major product of the O2*--mediated oxidation of 5-HT is tryptamine-4,5-dione (T-4, 5-D). However, O2*- and H2O2, cogenerated by the xanthine oxidase-mediated oxidation of xanthine to uric acid, together react with trace levels of iron that contaminate buffer constituents to give a chemically ill-defined oxo-iron species. This species mediates the oxidation of 5-HT to a C(4)-centered carbocation intermediate that reacts with 5-HT to give 5,5'-dihydroxy-4, 4'-bitryptamine (4,4'-D) and with uric acid to give 9-[3-(2-aminoethyl)-5-hydroxy-1H-indol-4-yl]-2,6,8-triketo-1H,3H, 7H-purine (7) as the major products. These products differ from those formed in the HO*-mediated oxidation of 5-HT under similar conditions. When the reaction is carried out in the presence of the intraneuronal nucleophile glutathione (GSH), T-4,5-D is scavenged to give 7-(S-glutathionyl)tryptamine-4,5-dione, whereas the putative carbocation intermediate is scavenged to give 4-(S-glutathionyl)-5-hydroxytryptamine. T-4,5-D also reacts with the sulfhydryl residues of a model protein, alcohol dehydrogenase, and inhibits its activity. Previous investigators have proposed that T-4, 5-D is a serotonergic neurotoxin. This raises the possibility that T-4,5-D and perhaps other putative intraneuronal metabolites formed by the O2*-/H2O2/oxo-iron-mediated oxidations of 5-HT might be endotoxins that contribute to neurodegeneration in brain regions innervated by serotonergic neurons caused by MA, ischemia-reperfusion, and other neurodegenerative brain disorders.
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PMID:Oxidation of serotonin by superoxide radical: implications to neurodegenerative brain disorders. 962 32

Ingested ethanol is transported to the colon via blood circulation, and intracolonic ethanol levels are equal to those of the blood ethanol levels. In the large intestine, ethanol is oxidized by colonic bacteria, and this can lead to extraordinarily high acetaldehyde levels that might be responsible, in part, for ethanol-associated carcinogenicity and gastrointestinal symptoms. It is believed that bacterial acetaldehyde formation is mediated via microbial alcohol dehydrogenases (ADHs). However, almost all cytochrome-containing aerobic and facultative anaerobic bacteria possess catalase activity, and catalase can, in the presence of hydrogen peroxide (H2O2), use several alcohols (e.g., ethanol) as substrates and convert them to their corresponding aldehydes. In this study we demonstrate acetaldehyde production from ethanol in vitro by colonic contents in a reaction catalyzed by both bacterial ADH and catalase. The amount of acetaldehyde produced by the human colonic contents was proportional to the ethanol concentration, the amount of colonic contents, and the length of incubation time, even in the absence of added nicotinamide adenine dinucleotide or H2O2. The catalase inhibitors sodium azide and 3-amino-1,2,4-triazole (3-AT) markedly reduced the amount of acetaldehyde produced from 22 mM ethanol in a concentration dependent manner compared with the control samples (0.1 mM sodium azide to 73% and 10 mM 3-AT to 67% of control). H2O2 generating system [beta-D(+)-glucose + glucose oxidase] and nicotinamide adenine dinucleotide induced acetaldehyde formation up to 6- and 5-fold, respectively, and together these increased acetaldehyde formation up to 11-fold. The mean supernatant catalase activity was 0.53+/-0.1 micromol/min/mg protein after the addition of 10 mM H2O2, and there was a significant (p < 0.05) correlation between catalase activity and acetaldehyde production after the addition of the hydrogen peroxide generating system. Our results demonstrate that colonic contents possess catalase activity, which probably is of bacterial origin, and indicate that in addition to ADH, part of the acetaldehyde produced in the large intestine during ethanol metabolism can be catalase dependent.
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PMID:Role of catalase in in vitro acetaldehyde formation by human colonic contents. 972 83

The reaction between allicin (diallylthiosulfinate), the active component of garlic and reduced glutathione was investigated. The product of this reaction, mixed disulfide S-allylmercaptoglutathione (GSSA) was separated by high performance liquid chromatography and identified by 1H and (13)C nuclear magnetic resonance and mass spectroscopy. The reaction is fast (with an apparent bimolecular reaction rate constant of 3.0 M(-1) s(-1)). It is pH-dependent, which reveals a direct correlation to the actual concentration of mercaptide ion (GS(-)). Both GSSA and S-allylmercaptocysteine (prepared from allicin and cysteine) reacted with SH-containing enzymes, papain and alcohol dehydrogenase from Thermoanaerobium brockii yielding the corresponding S-allylmercapto proteins, and caused inactivation of the enzymes. The activity was restored with dithiothreitol or 2-mercaptoethanol. In addition, GSSA also exhibited high antioxidant properties. It showed significant inhibition of the reaction between OH radicals and the spin trap 5,5'-dimethyl-1-pyroline N-oxide in the Fenton system as well as in the UV photolysis of H2O2. In ex vivo experiments done with fetal brain slices under iron-induced oxidative stress, GSSA significantly lowered the production levels of lipid peroxides. The similar activity of GSSA and allicin as SH-modifiers and antioxidants suggests that the thioallyl moiety has a key role in the biological activity of allicin and its derivatives.
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PMID:S-Allylmercaptoglutathione: the reaction product of allicin with glutathione possesses SH-modifying and antioxidant properties. 1111 47

Creatine kinase (CK) was used as a marker molecule to examine the side effect of damage to tissues by indomethacin (IM), an effective drug to treat rheumatoid arthritis and gout, with horseradish peroxidase and hydrogen peroxide (HRP-H2O2). IM inactivated CK during its interaction with HRP-H2O2. Under aerobic conditions, inactivation of CK significantly decreased. CK in rat heart homogenate was also inactivated by IM with HRP-H2O2. When IM was incubated with HRP-H2O2, the maximum absorption of IM at 280 nm rapidly decreased and a new peak at 410 nm occurred with isosbestic points at 260 and 312 nm. In contrast, under anaerobic conditions, the spectral change of IM was almost absent, indicating IM was oxidized to the yellow substance by HRP-H2O2. Adding catalase strongly inhibited the production of yellow substance. Sodium azide also blocked the formation of yellow substance and the inactivation of CK. Electron spin resonance signals of IM carbon-centered radical were detected using 2-methyl-2-nitrosopropane during the interaction of IM with HRP-H2O2 under anaerobic conditions. Oxygen was consumed during the interaction of IM with HRP-H2O2. These results suggest that IM carbon-centered radicals may rapidly react with O2 to generate the peroxyl radicals. Sulfhydryl groups and tryptophane residues of CK decreased during the interaction of IM with HRP-H2O2. Other sulfhydryl enzymes, including alcohol dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase, were also readily inactivated during the interaction with HRP-H2O2. Sulfhydryl enzymes seem to be very sensitive to IM activated by HRP-H2O2.
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PMID:Inactivation of creatine kinase during the interaction of indomethacin with horseradish peroxidase and hydrogen peroxide: involvement of indomethacin radicals. 1124 19

Compounds acting as antioxidants to lipids often have a prooxidant effect on DNA or protein. In this study, inactivation of creatine kinase was examined as an indicator of protein damage induced by antioxidative stilbene derivatives, including diethylstilboestrol, resveratrol and tamoxifen, with horseradish peroxidase and hydrogen peroxide (horseradish peroxidase-H2O2). Diethylstilboestrol and resveratrol, but not tamoxifen, rapidly inactivated creatine kinase. Also, creatine kinase in heart homogenate was inactivated by diethylstilboestrol and resveratrol. Tamoxifen, which has no phenolic hydroxyl groups in its structure, was about 10 times less active in protecting lipids and creatine kinase than diethylstilboestrol and resveratrol, suggesting that phenolic hydroxyl groups in diethylstilboestrol and resveratrol of stilbene derivatives are anti- and pro-oxidative. Absorption spectra of these stilbene derivatives rapidly changed during the reaction with horseradish peroxidase-H202. Diethylstilboestrol and resveratrol free radicals emitted electron spin resonance signals and creatine kinase effectively diminished the electron spin resonance signals. These results suggest that free radicals of diethylstilboestrol and resveratrol formed through reaction with horseradish peroxidase-H202 inactivated creatine kinase. Presumably, oxidation of essential cysteine and tryptophan residues lead to inactivation of creatine kinase. Other enzymes, including alcohol dehydrogenase and cholinesterase, were also sharply inhibited by diethylstilboestrol and resveratrol with horseradish peroxidase-H202. Free radicals of diethylstilboestrol and resveratrol seem to mediate between anti- and prooxidative actions.
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PMID:Inactivation of creatine kinase induced by stilbene derivatives. 1207 28


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