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)

It has been suggested that in the chloramphenicol-induced aplastic anemia nitrosochloramphenicol may be involved as a toxic intermediate. We found that aminochloramphenicol, which reportedly is formed from chloramphenicol by intestinal bacteria, is N-oxygenated by liver microsomes of untreated rats with apparent Km = 0.4 mM and Vmax = 0.28 nmole/min/mg protein. These values are in close agreement with those reported for aniline N-oxygenation. Reductive reactions, however, eliminate the N-oxygenation products at markedly higher rates. As judged from hemoglobin-free single-pass liver perfusion experiments, N-hydroxy-chloramphenicol is reduced at rates faster than 300 nmole/min/g liver wet, and nitrosochloramphenicol is eliminated at rates faster than 1.5 mumole/min/g liver. At least two NADPH- and two NADH-dependent cytosolic enzymes are responsible for nitrosochloramphenicol reduction. Determination of the kinetic parameters of these enzymes by stop-flow analysis revealed the contribution of enzymes, one of it being alcohol dehydrogenase, with Michaelis constants in the micromolar range. Despite this high reducing capacity, about 10% of nitrosochloramphenicol reacted with GSH under formation of glutathionesulfinamidochloramphenicol and GSSG released from the liver into bile and venous effluent. At high nitrosochloramphenicol load these reactions led to glutathione depletion of the liver, caused membrane damage, and impaired bile production. At low nitrosochloramphenicol load, i.e. below 0.5 mumole/min/g, no relevant nitrosochloramphenicol passed the liver. These data together with the previously reported reactions of nitrosochloramphenicol within human blood suggest that nitrosochloramphenicol, if formed at all in the intestine or liver, is rather unlikely to be transferred to the critical target.
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PMID:Formation and disposition of nitrosochloramphenicol in rat liver. 405 15

It has previously been shown that radioinduced organic radicals can be repaired by hydrogen donation from glutathione (GSH) and this repair is in competition with oxygen (damage fixation). In this paper the influence of exogenous glutathione on the radiation response of the enzyme alcohol dehydrogenase (YADH), DNA in vitro, and E. coli B/r cells has been investigated. GSH is observed to protect YADH essentially by free radical scavenging mechanisms in both presence or absence of oxygen. The same mechanism seems operate in the radioprotection afforded by GSH to DNA in vitro. E. coli B/r cells are protected at higher extent by GSH than its oxidized form (GSSG); the possibility that GSH penetrate into bacterial cells more easily that GSSG can explain their different behaviour. None of the three systems studied has provided definitive support for the occurrence of the hydrogen donation reaction in the radioprotective mechanisms of GSH versus biomolecules and bacterial cells.
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PMID:Role of glutathione in affecting the radiosensitivity of molecular and cellular systems. 635 35

1. Ethanol induces a decrease in GSH (reduced glutathione) concentration is isolated hepatocytes. Maximal effects appear at 20 mM-ethanol. The concentration-dependence of this decrease is paralleled by the concentration-dependence of the activity of alcohol dehydrogenase. 2. Pyrazole, a specific inhibitor of alcohol dehydrogenase, prevents the ethanol-induced GSH depletion. 3. Acetaldehyde, above 0.05 mM, also promotes a decrease in GSH concentration in hepatocytes. 4. Disulfiram (0.05 mM), an inhibitor of aldehyde dehydrogenase, potentiates the fall in GSH concentration caused by acetaldehyde. 5. The findings support the hypothesis that acetaldehyde is responsible for the depletion of GSH induced by ethanol. 6. Methionine prevents the effect of alcohol or acetaldehyde on GSH concentration in hepatocytes.
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PMID:Effect of ethanol on glutathione concentration in isolated hepatocytes. 699 18

As a fraction of ingested ethanol (EtOH) is metabolized by gastric mucosa, different amounts of alcohol reach the liver, when the same dose is administered by oral or intravenous route. In previous experiments, we demonstrated that the decrease of hepatic reduced glutathione (GSH) is less pronounced and is followed by a quicker recovery after oral than after intraperitoneal administration of the same amount of EtOH. Therefore, the time-course of hepatic GSH concentration seems to be an indirect assay of EtOH metabolism by the liver. On the basis of these findings, any condition causing a reduced function of gastric alcohol dehydrogenase (ADH) should show up as a more severe depletion of hepatic GSH. In the same rat experimental model we determined the effects of cimetidine and omeprazole administration on gastric ADH activity and on the time-course of hepatic GSH after EtOH load. Cimetidine was shown to inhibit gastric ADH with a Ki of 0.167 +/- 0.009 mmol l-1; accordingly, the pretreatment with this drug (20 mg kg-1 b.w. per day for 1 week) determined, after oral EtOH load, a marked reduction of hepatic GSH, likewise after intraperitoneal administration. Omeprazole exerted only a marginal inhibition on gastric ADH and this drug (0.3 mg kg-1 b.w. per day for 1 week) did not modify the time-course of hepatic GSH concentrations after EtOH load. This study indicates that the inhibition of gastric ADH, when associated with EtOH intake, induces depletion of the hepatic GSH concentration and, therefore, possible liver damage.
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PMID:Hepatic glutathione after ethanol administration in rat: effects of cimetidine and omeprazole. 747 28

As a fraction of ingested ethanol is metabolized by gastric mucosa, different amounts of alcohol should reach the liver when the same dose is administered by oral or intravenous route. Therefore, we investigated the time-course of hepatic reduced glutathione (GSH) concentrations after intra-peritoneal or intra-gastric load of the same amount of ethanol in the rat. The test was also performed in fasted and Cimetidine-treated rats. The oral ethanol administration was followed by a less pronounced decrease and by a quicker recovery of hepatic content of GSH than after intraperitoneal route. In the fasted rat, basal hepatic GSH significantly decreased; after alcohol administration the decrease of hepatic GSH was more severe and prolonged than in the fed rat. Cimetidine was shown to be a potent inhibitor of gastric ADH. Pre-treatment with Cimetidine did not change the basal levels of hepatic GSH, but after oral ethanol load, the decrease of the hepatic GSH content was significantly (p < 0.005) more pronounced than in controls. This study demonstrates the beneficial effects of gastric ethanol metabolism on the liver. The reduced gastric ethanol metabolism, induced by fasting or by Cimetidine resulted in a decreased content and delayed recovery of liver GSH content.
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PMID:Hepatic glutathione determination after ethanol administration in rat: evidence of the first-pass metabolism of ethanol. 782 83

Mechanisms of the hepatotoxicity of ethanol are reviewed, including effects resulting from alcohol dehydrogenase (ADH) mediated excessive hepatic generation of NADH and acetaldehyde. Gastric ADH explains first-pass metabolism by ethanol; its activity is low in alcoholics and in females and is decreased by some commonly used drugs. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last 25 years have culiminated in the molecular elucidation of the ethanol-inducible cytochrome P-450 (2E1) which causes metabolic tolerance to ethanol and to various commonly used medications, enhanced degradation of testosterone and vitamin A (with vitamin A depletion) and selective hepatic perivenular toxicity. The latter results from free radical generation and activation of various xenobiotics, causing increased vulnerability of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens and even nutritional factors such as vitamin A and beta-carotene. Furthermore, induction of the microsomal pathway contributes to increased acetaldehyde generation which promotes GSH depletion and lipid peroxidation and other toxic effects. Nutritional deficits may affect the toxicity of ethanol and acetaldehyde, as illustrated by the depletion in glutathione, ameliorated by S-adenosyl-L-methionine. Other 'supernutrients' include polyenylphosphatidylcholine, shown to correct the alcohol-induced hepatic phosphatidylcholine depletion and to prevent alcoholic cirrhosis in non-human primates.
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PMID:Hepatic and metabolic effects of ethanol: pathogenesis and prevention. 782 92

It has previously been reported that isolated rat hepatocytes rapidly and completely metabolize high concentrations of 4-hydroxy-2,3-(E)-nonenal (4-HNE). However, until this report, the degree to which oxidative-reductive and nonoxidative metabolic pathways function in the depletion of 4-HNE by isolated rat hepatocytes has been speculative. The objective of the present study was to quantitate the extent to which cellular aldehyde dehydrogenases (ALDH; EC 1.2.1.3.), alcohol dehydrogenase (ADH; EC 1.1.1.1.), and glutathione S-transferases (GST; EC 2.5.1.18) function simultaneously during hepatocellular metabolism of 4-HNE. Hepatocytes were incubated with varying concentrations of 4-HNE (50, 100, 250 microM) and reversed-phase HPLC was used to quantitate 4-HNE and the oxidative and reductive metabolites, 4-hydroxy-2-nonenoic acid and 1,4-dihydroxy-2-nonene, respectively. Conjugative metabolism of 4-HNE was determined from the depletion of cellular reduced glutathione (GSH) and concomitant formation of a GSH-4-HNE adduct detected as 2,4-dinitrofluorobenzene derivatives measured by reversed-phase HPLC. Hepatocellular elimination of 4-HNE was estimated at rates of 1.666, 0.902, and 0.219 nmol min-1 10(6) hepatocytes-1 for 50, 100, and 250 microM aldehyde, respectively. At aldehyde concentrations of 50, 100, and 250 microM the maximal concentrations of oxidative (acid) metabolites formed were 5.9, 12.7, and 28.9 nmoles 10(6) hepatocytes-1, whereas the concentrations of the reductive (diol) metabolite were 0.4, 12.6, and 42.3 nmoles 10(6) hepatocytes-1, respectively. The presence of 4-methylpyrazole or cyanamide abolished formation of the reductive metabolite 1,4-dihydroxy-2-nonene or the oxidative metabolite 4-hydroxy-2-nonenoic acid in hepatocyte suspensions. At all 4-HNE concentrations evaluated, hepatocellular glutathione was not completely depleted by the aldehyde and the depletion of cellular reduced GSH corresponded to the production of the GSH-4-HNE conjugate. Metabolism by the alcohol/aldehyde dehydrogenase pathways accounted for approximately 10% of the 4-HNE elimination, while bioconversion by GST represent 50-60% of the total 4-HNE removal by hepatocytes. The enzymatic pathways responsible for the remaining 40% of 4-HNE metabolism remain to be identified. Taken together these results describe the quantitative and dynamic importance of oxidative, reductive, and nonoxidative routes in the metabolism and detoxification of 4-HNE.
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PMID:The hepatocellular metabolism of 4-hydroxynonenal by alcohol dehydrogenase, aldehyde dehydrogenase, and glutathione S-transferase. 784 Jun 16

The relative contribution of the aldehyde dehydrogenase (EC 1.2.1.3, ALDH) and glutathione (GSH) conjugate system to the degradation of (E)-4-hydroxy-2-nonenal (4HN), a toxic breakdown product arising from lipid peroxidation, was investigated in rat liver. Significant increases in the contents of 4HN and hexanal (HA) and a decrease of ALDH but not alcohol dehydrogenase (EC 1.1.1.2, ADH) activity were recognized in rat liver following administration of carbon tetrachloride (3 ml/kg, p.o.). Hepatic ALDH activity was correlated with HA production (r = -0.82, P < 0.01) but not with 4HN. When lipid peroxidation was induced by t-butyl hydroperoxide, the ratio of HA to 4HN production in the liver of rats pretreated with the ALDH inhibitor, cyanamide (100 mg/kg, i.p.) was higher than that in controls, whereas the ratio was lower in the liver of rats pretreated with the glutathione-depleting agent, phorone (250 mg/kg, i.p.). These results suggest that 4HN in rat liver is metabolized by the GSH-conjugate system in preference to degradation by ALDH.
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PMID:Effects of aldehyde dehydrogenase and glutathione on the degradation of (E)-4-hydroxy-2-nonenal and N-hexanal in rat liver. 803 11

The oxidative metabolism of low molecular weight, saturated and unsaturated, primary alcohols, which include ethanol, allyl alcohol (2-propen-1-ol), and propargyl alcohol (2-propyn-1-ol), is generally accepted to occur via alcohol dehydrogenase; however, compared to other short-chain alcohols, 2-propyn-1-ol is a poor substrate for this enzyme. Accordingly, we have examined liver catalase as an alternative pathway for the oxidation or bioactivation of 2-propyn-1-ol to 2-propyn-1-al, a highly reactive alpha,beta-unsaturated aldehyde. The rates of oxidation for a series of low molecular weight, saturated, primary alcohols and selected unsaturated alcohols were determined for the bovine liver catalase-catalyzed reaction by measuring aldehyde production over time employing a GC procedure. A negative correlation was found for log rates of oxidation versus molecular size (volume) of the substrates (p < 0.01); however, the rate of oxidation for 2-propyn-1-ol was higher than predicted by this relation and was 30% greater than the oxidation rate determined for ethanol. In addition, 2-propyn-1-ol-derived 2-propyn-1-al inhibited the peroxidatic and catalytic activities of catalase, whereas 2-propen-1-ol-derived 2-propen-1-al had no effect on these activities of catalase. Inhibition was blocked by GSH; and the activity was not restored to the inhibited enzyme by GSH treatment or dialysis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative oxidation of 2-propyn-1-ol with other low molecular weight unsaturated and saturated primary alcohols by bovine liver catalase in vitro. 807 74

2-Chloroacetaldehyde (CAA)-induced cytotoxicity in isolated hepatocytes was enhanced markedly if hepatocyte alcohol or aldehyde dehydrogenase was inhibited prior to CAA addition. Hepatocyte GSH depletion, ATP depletion and lipid peroxidation by CAA were also enhanced markedly. Furthermore, CAA was about 10- and 70-fold more cytotoxic than its oxidative or reductive metabolite chloroacetate or chloroethanol, respectively. Nutrients such as lactate, xylitol, sorbitol or glycerol, which increase cytosolic NADH levels, prevented CAA cytotoxicity in normal hepatocytes but further enhanced cytotoxicity toward alcohol dehydrogenase inactivated hepatocytes, suggesting that increased cytosolic NADH reduces CAA via alcohol dehydrogenase in normal hepatocytes but prevents CAA oxidation in alcohol dehydrogenase inactivated hepatocytes. However, increasing cytosolic NADH levels with ethanol or NADH-generating nutrients after CAA had been metabolized also prevented cytotoxicity and caused a partial ATP recovery, whereas oxidation of cytosolic NADH with pyruvate markedly increased cytotoxicity. This indicates that cytotoxic CAA concentrations cause oxidative stress and that ATP levels can be restored if cellular redox homeostasis is normalized with reductants. Furthermore, except for fructose, nutrients that did not increase NADH did not affect CAA-induced cytotoxicity. Fructose also caused a partial ATP recovery, and its protection was prevented by the glycolytic inhibitor fluoride. Hepatocytes isolated from fasted animals were 4- to 6-fold more susceptible to CAA-induced ATP depletion and cytotoxicity. No lipid peroxidation occurred at these lower CAA concentrations. Furthermore, all nutrients, including alanine, glutamine and glucose, prevented cytotoxicity toward hepatocytes isolated from fasted animals. The susceptibility of hepatocytes to CAA cytotoxicity, therefore, depends on both cellular redox homeostasis and cellular energy supply.
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PMID:Chloroacetaldehyde-induced hepatocyte cytotoxicity. Mechanisms for cytoprotection. 809 90


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