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)

We previously showed that theanine, is a major amino acid in green tea, enhanced doxorubicin (DOX) induced antitumor activity. Besides, theanine induced the elevation of glutathione (GSH) level attributable to the increase of glutamate in the liver of mice, namely theanine would reduce the adverse reaction of DOX. Consequently, theanine was thought to be effective against the tissue changes with GSH level reduction. On the other hand, it is suggested excessive uptake of alcohol causes a production of free radicals, a decrease of GSH level, and an increase in the amount of lipid peroxide (LPO) in liver, and shifting to an alcoholic liver injury. Then, aiming at the prevention and medical treatment of a hepatic toxicity by the food components with little toxicity, we have studied the effect of theanine (i.p.) on ethanol metabolism and hepatic toxicity using ethanol (p.o.) single-administered mice. On the 1st hour after ethanol administration, the ethanol concentrations in blood of the theanine combined groups decreased compared with the ethanol-alone group. The alcohol dehydrogenase and aldehyde dehydrogenase activities in the liver increased by combined theanine. Since the elevation of cytochrome P450 (CYP) 2E1 activity was controlled in the theanine-combined groups, it was considered that these disorders attributable to CYP2E1 in ethanol long-term uptake might be avoidable by theanine. Although LPO increased in 3 h after by single-administration of ethanol, the increase was controlled by theanine-administration and was improved until the normal level. In conclusion, it was indicated that theanine was effective against alcoholic liver injury.
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PMID:Effects of theanine on alcohol metabolism and hepatic toxicity. 1614 43

During growth on ethanolamine, Salmonella enterica synthesizes a multimolecular structure that mimics the carboxysome used by some photosynthetic bacteria to fix CO(2). In S. enterica, this carboxysome-like structure (hereafter referred to as the ethanolamine metabolosome) is thought to contain the enzymatic machinery needed to metabolize ethanolamine into acetyl coenzyme A (acetyl-CoA). Analysis of the growth behavior of mutant strains of S. enterica lacking specific functions encoded by the 17-gene ethanolamine utilization (eut) operon established the minimal biochemical functions needed by this bacterium to use ethanolamine as a source of carbon and energy. The data obtained support the conclusion that the ethanolamine ammnonia-lyase (EAL) enzyme (encoded by the eutBC genes) and coenzyme B(12) are necessary and sufficient to grow on ethanolamine. We propose that the EutD phosphotransacetylase and EutG alcohol dehydrogenase are important to maintain metabolic balance. Glutathione (GSH) had a strong positive effect that compensated for the lack of the EAL reactivase EutA protein under aerobic growth on ethanolamine. Neither GSH nor EutA was needed during growth on ethanolamine under reduced-oxygen conditions. GSH also stimulated growth of a strain lacking the acetaldehyde dehydrogenase (EutE) enzyme. The role of GSH in ethanolamine catabolism is complex and requires further investigation. Our data show that the ethanolamine metabolosome is not involved in the biochemistry of ethanolamine catabolism. We propose the metabolosome is needed to concentrate low levels of ethanolamine catabolic enzymes, to keep the level of toxic acetaldehyde low, to generate enough acetyl-CoA to support cell growth, and to maintain a pool of free CoA.
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PMID:Minimal functions and physiological conditions required for growth of salmonella enterica on ethanolamine in the absence of the metabolosome. 1629 77

Fifty years ago the dogma prevailed that alcohol was not toxic to the liver and that alcoholic liver disease was exclusively a consequence of nutritional deficiencies. We showed, however, that liver pathology developed even in the absence of malnutrition. This toxicity of alcohol was linked to its metabolism via alcohol dehydrogenase which converts nicotinamide adenine dinucleotide (NAD) to nicotinamide adenine dinucleotide-reduced form (NADH) which contributes to hyperuricemia, hypoglycemia and hepatic steatosis by inhibiting lipid oxidation and promoting lipogenesis. We also discovered a new pathway of ethanol metabolism, the microsomal ethanol oxidizing system (MEOS). The activity of its main enzyme, cytochrome P4502E1 (CYP2E1), and its gene are increased by chronic consumption, resulting in metabolic tolerance to ethanol. CYP2E1 also detoxifies many drugs but occasionally toxic and even carcinogenic metabolites are produced. This activity is also associated with the generation of free radicals with resulting lipid peroxidation and membrane damage as well as depletion of mitochondrial reduced glutathione (GSH) and its ultimate precursor, namely methionine activated to S-adenosylmethionine (SAMe). Its repletion restores liver functions. Administration of polyenylphosphatidylcholine (PPC), a mixture of unsaturated phosphatidylcholines (PC) extracted from soybeans, restores the structure of the membranes and the function of the corresponding enzymes. Ethanol impairs the conversion of beta-carotene to vitamin A and depletes hepatic vitamin A and, when it is given together with vitamin A or beta-carotene, hepatotoxicity is potentiated. Our present therapeutic approach is to reduce excess alcohol consumption by the Brief Intervention technique found to be very successful. We correct hepatic SAMe depletion and supplementation with PPC has some favorable effects on parameters of liver damage which continue to be evaluated. Similarly dilinoleoylphosphatidylcholine (DLPC), PPC's main component, also partially opposes the increase in CYP2E1 by ethanol. Hence, therapy with SAMe +DLPC is now being considered.
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PMID:Pathogenesis and treatment of alcoholic liver disease: progress over the last 50 years. 1636 67

We studied changes in the antioxidant systems involved in hepatoprotection after ethanol exposure in primary culture of mouse hepatocytes. Ethanol decreased glutathione (GSH) levels and the S-adenosylmethionine (SAMe) to S-adenosylhomocysteine (SAH) ratio by 53% and 22%, respectively. Cytosolic glutathione S-transferase (GST) activity was significantly lower in ethanol exposed hepatocytes, which was accompanied by an increase in GST activity in the culture medium. When specific substrates for mu- and pi-class GST were utilized, ethanol significantly decreased the mu- and pi-class GST activity by 53% and 13%, respectively. Lipid peroxidation (LPO), assessed by the thiobarbituric acid assay, increased to 221% of control by ethanol and was potentiated by cyanamide, an aldehyde dehydrogenase inhibitor. The changes in LPO, cytosolic GST activity, GSH levels and SAMe/SAH ratio in ethanol exposed hepatocytes were completely or partially reversed by either Vitamin E or 4-methylpyrazole, an alcohol dehydrogenase (ADH) inhibitor. Retinoid X receptor alpha-deficient (RXRalpha KO) mice, which are more susceptible to ethanol-induced liver toxicity, have decreased pi-class GST (56%), mu-class GST (28%), and glutathione peroxidase (35%) activities compared with wild type. Taken together, primary hepatocyte provides a valuable model to analyze ethanol-induced oxidative stress. The inhibition of mu-class GST activity by ethanol and the decreased pi-class GST activity in RXRalpha KO mice implicate the importance of these isozymes in ethanol detoxification process.
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PMID:The effect of ethanol, ethanol metabolizing enzyme inhibitors, and Vitamin E on regulating glutathione, glutathione S-transferase, and S-adenosylmethionine in mouse primary hepatocyte. 1654 Mar 68

The effect of Sorbus commixta cortex, a traditional herbal medicine used for the treatment of bronchitis, gastritis and dropsy, on blood alcohol concentration (BAC) and hepatic lipid peroxidation was examined in acute alcohol-treated rats. A 30-min pretreatment with a methanol extract of S. commixta cortex (SC) at concentrations higher than 200 mg kg(-1) resulted in a significant decrease in BAC and the ethyl acetate fraction (SE) of the extract showed the highest potency, with a maximum of a 46% decrease at 150 mg kg(-1) 2 h after alcohol administration (3.0 g kg(-1)) compared with the control group (P < 0.005). The rapid reduction in BAC did not appear to be due to the protection or activation of hepatic alcohol dehydrogenase (ADH) activity by SE. Hepatic malondialdehyde (MDA) levels were significantly increased by acute alcohol administration within 6 h, although pretreatment with the SE caused a significant decrease in MDA levels compared with alcohol treatment alone. Hepatic glutathione (GSH) levels and superoxide dismutase (SOD) activity remained unchanged by alcohol, SE alone or by the combined treatment of alcohol and SE. However, catalase activity was significantly reduced by acute alcohol administration and pretreatment with the SE led to significant protection of its activity. These results suggest that pretreatment with SE reduces hepatic lipid peroxidation by decreasing the bioavailability of alcohol and its oxidative metabolites, such as H2O2, at least partly, through the protection of hepatic catalase in acute alcohol-treated rats.
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PMID:The pharmacological potential of Sorbus commixta cortex on blood alcohol concentration and hepatic lipid peroxidation in acute alcohol-treated rats. 1664 Aug 38

A self-cloning module for gene knock-out and knock-in in industrial brewing yeast strain was constructed that contains copper resistance and gamma-glutamylcysteine synthetase gene cassette, flanked by alcohol dehydrogenase II gene (ADH2) of Saccharomyces cerevisiae. The module was used to obtain recombined strains RY1 and RY2 by targeting the ADH2 locus of host Y1. RY1 and RY2 were genetically stable. PCR and enzyme activity analysis of RY1 and RY2 cells showed that one copy of ADH2 was deleted by GSH1+CUP1 insertion, and an additional copy of wild type was still present. The fermentation ability of the recombinants was not changed after genetic modification, and a high level of glutathione (GSH) was secreted, resulting from GSH1 overexpression, which codes for gamma-glutamylcysteine synthetase. A pilot-scale brewing test for RY1 and RY2 indicated that acetaldehyde content in fermenting liquor decreased by 21-22%, GSH content increased by 20-22% compared with the host, the antioxidizability of the recombinants was improved, and the sensorial evaluation was also better than that of the host. No heterologous DNA was harbored in the recombinants; therefore, they could be applied in the beer industry in terms of their biosafety.
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PMID:Recombinant industrial brewing yeast strains with ADH2 interruption using self-cloning GSH1+CUP1 cassette. 1934 81

Hepatocyte growth factor (HGF) is involved in many cellular responses, such as mitogenesis and apoptosis protection; however, its effect against oxidative injury induced by ethanol metabolism is not well understood. The aim of this work was to address the mechanism of HGF-induced protection against ethanol-generated oxidative stress damage in the human cell line VL-17A (cytochrome P450 2E1/alcohol dehydrogenase-transfected HepG2 cells). Cells were pretreated with 50 ng/ml HGF for 12 h and then treated with 100 mM ethanol for 0-48 h. Some parameters of oxidative damage were evaluated. We found that ethanol induced peroxide formation (3.3-fold) and oxidative damage as judged by lipid peroxidation (5.4-fold). Damage was prevented by HGF. To address the mechanisms of HGF-induced protection we investigated the cellular antioxidant system. We found that HGF increased the GSH/GSSG ratio, as well as SOD1, catalase, and gamma-glutamylcysteine synthetase expression. To explore the signaling pathways involved in this process, VL-17A cells were pretreated with inhibitors against PI3K, Akt, and NF-kappaB. We found that all treatments decreased the expression of the antioxidant enzymes, thus abrogating the HGF-induced protection against oxidative stress. Our results demonstrate that HGF protects cells from the oxidative damage induced by ethanol metabolism by a mechanism driven by NF-kappaB and PI3K/Akt signaling.
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PMID:Hepatocyte growth factor protects hepatocytes against oxidative injury induced by ethanol metabolism. 1946 46

Methanol, when introduced into all mammals, is oxidized into formaldehyde and then into formate, mainly in the liver. Such metabolism is accompanied by the formation of free radicals. In all animals, methanol oxidation, which is relatively slow, proceeds via the same intermediary stages, usually in the liver, and various metabolic systems are involved in the process, depending on the animal species. In nonprimates, methanol is oxidized by the catalase-peroxidase system, whereas in primates, the alcohol dehydrogenase system takes the main role in methanol oxidation. The first metabolite (formaldehyde is rapidly oxidized by formaldehyde dehydrogenase) is the reduced glutathione (GSH)-dependent enzyme. Generated formic acid is metabolized into carbon dioxide with the participation of H 4 folate and two enzymes, 10-formyl H 4 folate synthetase and dehydrogenase, whereas nonprimates oxidize formate efficiently. Humans and monkeys possess low hepatic H 4 folate and 10-formyl H 4 folate dehydrogenase levels and are characterized by the accumulation of formate after methanol intoxication. The consequences of methanol metabolism and toxicity distinguish the human and monkey from lower animals. Formic acid is likely to be the cause of the metabolic acidosis and ocular toxicity in humans and monkeys, which is not observed in most lower animals. Nevertheless, chemically reactive formaldehyde and free radicals may damage most of the components of the cells of all animal species, mainly proteins and lipids. The modification of cell components results in changes in their functions. Methanol intoxication provokes a decrease in the activity and concentration of antioxidant enzymatic as well as nonenzymatic parameters, causing enhanced membrane peroxidation of phospholipids. The modification of protein structure by formaldehyde as well as by free radicals results changes in their functions, especially in the activity of proteolytic enzymes and their inhibitors, which causes disturbances in the proteolytic-antiproteolytic balance toward the proteolytics and enhances the generation of free radicals. Such a situation can lead to destructive processes because components of the proteolytic-antiproteolytic system during enhanced membrane lipid peroxidation may penetrate from blood into extracellular space, and an uncontrolled proteolysis can occur. This applies particularly to extracellular matrix proteins.
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PMID:Toxicological and metabolic consequences of methanol poisoning. 2002 Nov 53

Benzene exposure in occupational settings often occurs with concurrent exposure to toluene, the methyl-substituted derivative of benzene. Toluene is also readily metabolized by CYP450 isozymes although oxidation primarily occurs in the methyl group. While earlier mouse studies addressing co-exposure to benzene and toluene at high concentrations demonstrated a reduction in benzene-induced genotoxicity, we have previously found, using an intermittent exposure regimen with lower concentrations of benzene (50 ppm) and toluene (100 ppm), that toluene enhances benzene-induced clastogenic or aneugenic bone marrow injury in male CD-1 mice with significantly increased CYP2E1, and depleted GSH and GSSG levels. The follow-up study reported here also used the same daily and total co-exposures but over consecutive days and compared the effects of co-exposure on genotoxicity and metabolism in CD-1 mice both with and without buthionine sulfoximine (BSO) treatment to deplete GSH. In this study the toluene co-exposure doubled the genotoxic response (as determined by the erythrocyte micronucleus test) to benzene alone. Further, GSH depletion caused a reduction in this genotoxicity in both benzene exposed and benzene/toluene co-exposed mice. The results are discussed in terms of the analyses of urinary metabolites from this consecutive day study and the intermittent exposure study as well as levels of CYP2E1, epoxide hydrolase, quinone reductase, alcohol dehydrogenase, and aldehyde dehydrogenase activities. The results suggest that the presence of glutathione is necessary for benzene genotoxicity either as a metabolite conjugate or through an indirect mechanism such as TNF-induced apoptosis.
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PMID:Influence of toluene co-exposure on the metabolism and genotoxicity of benzene in mice using continuous and intermittent exposures. 2007 20

Quercetin, a natural compound of multiple origins, has broad biopharmacological effects, such as antioxidant, directly scavenging free radical, and hepatoprotectivity effects. This study is designed to investigate the interveneous effect of quercetin on liver injury induced by ethanol in rats. The rats that were orally treated with 50% ethanol for continuous ten days, which resulted in cell necrosis, fibrosis and inflammatory infiltration, were included in this study. Higher contents of AST, ALT ADH, gamma-GT, TG in plasma and MDA in liver tissue, and lower content of GSH in liver tissue were highlighted in ethanol-treated rats when compared with healthy ones. The levels of cytokines such as IL-1beta, IL-1, IL-6, IL-8, and TNF-alpha in rats plasma were also significantly enhanced, and level of IL-10 was obviously lowered through ethanol treatment. By preventive and synchronism treatment with quercetin for fourteen days, the contents of AST, ALT ADH, gamma-GT, TG and MDA, and levels of IL-1beta, IL-1, IL-6, IL-8, and TNF-alpha were significantly reduced, whereas GSH and level of IL-10 were obviously increased. It may be deduced that quercetin, by multiple mechanisms interplay, demonstrated somewhat protective effect on liver injury induced by ethanol in rats.
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PMID:Protective effects of quercetin on liver injury induced by ethanol. 2066 81


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