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)

Our objective was to determine if the previously reported protective effect of hypothyroidism against 1,1-dichloroethylene hepatotoxicity was associated with a change in distribution and covalent binding. Sprague-Dawley male rats were made hypothyroid (HypoT) by surgical thyroidectomy 2 weeks prior to studies and compared to euthyroid (EuT) rats. Hypothyroidism decreased body weights and liver to body weight ratios while mitochondrial non-protein sulfhydryl groups and cytosolic alcohol dehydrogenase activities were increased by 50%. Rats received a single oral dose of 100 mg [14C]1,1-dichloroethylene (DCE)/kg in mineral oil and were killed at 2, 4, 12 or 24 h; controls received mineral oil only. More rapid liver injury, as measured by serum alanine aminotransferase activity and histology, was present at 2 and 4 h after DCE in HypoT than EuT rats, but a similar magnitude of injury was evident at 12 and 24 h. DCE decreased liver non-protein sulfhydryl groups to a comparable extent in HypoT and EuT rats. Cytosolic glutathione S-transferase and alcohol dehydrogenase activities were decreased only in HypoT rats after DCE. HypoT rats excreted approximately 30% less total [14C]DCE-derived label in urine and their livers, kidneys and lungs consistently contained slightly less covalently bound [14C]DCE-derived label. In contrast, between 1 and 4 h after DCE, greater amounts of acid-soluble and acid-precipitable [14C]DCE-derived label were recovered in red blood cells of HypoT rats. Our results indicate that hypothyroidism did not protect against oral DCE hepatotoxicity but was associated with a more rapid injury at early times. Concurrently, hypothyroidism was found to change the fate of [14C]DCE with higher amounts of 14C-label recovered at early times in red blood cells while less 14C-label was excreted in urine and bound to liver.
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PMID:1,1-Dichloroethylene hepatotoxicity: hypothyroidism decreases metabolism and covalent binding but not injury in the rat. 176 16

Elevated levels of serum enzymes are frequently associated not only with alcohol-related organ damage but also with excessive alcohol consumption and alcoholism without significant tissue injury. However, both in the early detection of alcoholism as well as also in the diagnosis of alcohol-related diseases the sensitivities and specificities of these enzyme markers vary considerably. They may be influenced by nonalcohol-related diseases, enzyme-inducing drugs, nutritional factors, metabolic disorders, age, smoking, etc. Consequently, we have neither a single laboratory test--enzyme marker--nor a test combination that is reliable enough for the exact diagnosis between alcohol- and nonalcohol-related organ damage. In most cases it is possible to determine the tissue from which the elevated enzyme is derived, but only occasionally enzyme changes reflect the quantity of the tissue injury. Gamma-glutamyltransferase (GGT) is the most widely used laboratory marker of alcoholism and heavy drinking, detecting 34-85% of problem drinkers and alcoholics. However, the unspecificity of increased serum GGT limits its use for general screening purposes. Its value in the follow-up of various treatment programs, however, is well established. An elevated level of serum aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) in an alcoholic or a heavy consumer indicates alcohol-induced organ damage. The use of test combinations significantly improves the information received with single serum enzyme determinations. An ASAT/ALAT ratio greater than 1.5 can be considered as highly suggestive for the alcoholic etiology of the liver injury. Still better discrimination between alcoholic and nonalcoholic origin of the liver disease may be achieved by the determination of the ratio of GGT to alkaline phosphatase. If this ratio exceeds 1.4 the specificity of the finding in favor for alcoholic liver injury is 78%. The determination of the mitochondrial isoenzyme of ASAT also improves the diagnostic value of ASAT determination. The ratio of mitochondrial isoenzyme to total over 4 is highly suggestive for alcohol-related liver injury. In general, however, the determination of serum activities of other enzymes such as ornithine carbamyl transferase, lactate dehydrogenase, isocitrate dehydrogenase, sorbitol dehydrogenase, alcohol dehydrogenase, guanase, aldolase, alkaline phosphatase or glutathione S-transferase do not significantly improve the diagnostic information obtained with more conventional laboratory markers of liver injury.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Use of enzymes for the diagnosis of alcohol-related organ damage. 243 6

Using male Fischer 344 rats classified as young (2-4 months), middle aged (12-14 months), and old (22-25 months), the activities of several Phase I and Phase II biotransformation pathways in the large intestine were investigated, including benzo[a]pyrene hydroxylase (BPOH), alcohol dehydrogenase (ADH), glutathione S-transferase (GST), glutathione peroxidase (GSH-PX), beta-glucuronidase (BG), and microsomal and nuclear glucuronyltransferase (UDPGT). Levels of oxidized (GSSG) and reduced (GSH) glutathione and uridine 5'-diphosphoglucuronic acid (UDPGA) were also measured. BPOH increased 33% in old rats, while ADH and BG activity remained unchanged with age. Nuclear UDPGT remained unchanged with age, whereas form I of GSH-PX declined slightly in old rats. GST, microsomal UDPGT, and form II of GSH-PX declined by 38, 37 and 44%, respectively, in old rats. The decrease in GST and microsomal UDPGT was also significant in middle aged rats. Levels of colonic GSH, GSSG and UDPGA were found to be unchanged with age. These in vitro data suggest the possibility that if reactive intermediates are generated to the same extent in old rats as in young rats, decreased detoxification mechanisms in the old rat may increase susceptibility of the colon to actions of chemical carcinogens.
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PMID:Changes in phase I and phase II biotransformation with age in male Fischer 344 rat colon: relationship to colon carcinogenesis. 311 59

High concentrations of carbon disulfide in rat liver preparations do not change the activities of glutathione S-transferase, alcohol dehydrogenase, or aldehyde dehydrogenase and exert a slightly augmenting effect (not significant) on the activity of epoxide hydrolase. Carbon disulfide administered orally to rats in a high dose enhances the activity of hepatic epoxide hydrolase slightly (not significant), but has no influence on hepatic glutathione S-transferase in the cytosol and in microsomes. The results obtained in vitro and in vivo permit the assumption that occupational CS2-exposure does not appreciably inhibit the activities of epoxide hydrolase and glutathione S-transferase. The in-vitro findings with alcohol dehydrogenase and aldehyde dehydrogenase support the view held in the literature that the alcohol intolerance observed after occupational CS2-exposure ("Antabuse syndrome"-like reaction) is due to an inhibition of aldehyde dehydrogenase by CS2-metabolites of the thiocarbamate type.
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PMID:Behaviour of epoxide hydrolase, glutathione S-transferase, alcohol dehydrogenase, and aldehyde dehydrogenase, respectively, under the influence of carbon disulfide studies with rats in vivo and in vitro. 624 47

It is well established that many types of tumor cells have reduced lipid peroxidation capacity compared to their normal counterparts. Changes in the activity of enzymes metabolizing aldehydes produced by lipid peroxidation have also been reported in a variety of tumor cells. We have investigated the relationship between changes in lipid peroxidation and changes in aldehyde-metabolizing enzymes in normal hepatocytes and two representative rat hepatoma cell lines, McA-RH-7777 and JM2. Compared to hepatocytes, both 7777 and JM2 cells have significantly lower basal and prooxidant-induced levels of lipid peroxidation than normal hepatocytes. Using 4-hydroxynonenal (4-HNE) as substrate, both cell lines also have significantly reduced activities of alcohol dehydrogenase (ADH) and glutathione S-transferase (GST) compared to hepatocytes. JM2 cells have significantly increased aldehyde dehydrogenase (ALDH) and aldehyde reductase (ALRD) activities with 4-HNE. In 7777 cells the ALDH and ALRD activities are not different from hepatocytes. The changes in enzyme activity are inversely correlated with the sensitivity of cells to 4-HNE. JM2 cells, with increased ALDH and ALRD and decreased ADH and GST, are much more resistant to the toxic effects of 4-HNE than 7777 cells. Normal hepatocytes and JM2 cells are approximately equally resistant to 4-HNE even though hepatocytes rely primarily on GST-mediated aldehyde conjugation to metabolize 4-HNE. Coupled with previous results from our laboratories, the overall increased sensitivity of certain hepatoma cells to lipid aldehydes appears due to decreased ability of these hepatoma cells to remove toxic products of lipid peroxidation. Moreover, hepatoma cells with increased levels of aldehyde dehydrogenase and aldehyde reductase appear most like hepatocytes in their ability to metabolize lipid aldehydes.
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PMID:Role of aldehyde metabolizing enzymes in mediating effects of aldehyde products of lipid peroxidation in liver cells. 803 12

Ingestion of aflatoxin B1 (AFB1) represents a major risk factor in the aetiology of human hepatocellular carcinoma. In the rat, the harmful effects of AFB1 can be prevented by the administration of certain drugs which induce hepatic detoxification enzymes. We have previously shown that treatment of rats with the chemoprotector ethoxyquin (EQ) results in a marked increase in expression of the Alpha-class glutathione S-transferase (GST) Yc2 subunit which has high activity towards AFB1-8,9-epoxide [Hayes, Judah, McLellan, Kerr, Peacock and Neal (1991) Biochem. J. 279, 385-398]. To allow an assessment of whether the increased expression of GST Yc2 represents a general adaptive resistance mechanism to chemical stress, that is invoked by both chemoprotectors and carcinogens, we have examined the effects of EQ, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), phenobarbital (PB), AFB1, 3-methylcholanthrene (3-MC) and clofibrate on the AFB1-glutathione-conjugating activity and the GST subunit levels in rat liver. In addition, the effect of these drugs on the hepatic levels of an aldehyde reductase (AFB1-AR) that metabolizes the cytotoxic dialdehydic form of AFB1 has been studied as this enzyme also appears to be important in chemoprotection. Administration of the antioxidants EQ, BHA or BHT, as well as PB, led to a marked increase in levels of the GST Yc2 subunit in rat liver, and this increase coincided with a substantial rise in the GST activity towards AFB1-8,9-epoxide; neither AFB1, 3-MC nor clofibrate caused induction of Yc2 or any of the GST subunits examined. Among the xenobiotics studied, EQ was found to be the most effective inducing agent for the Yc2 subunit as well as Yc1, Yb1 and Yf. However, PB was equally as effective as EQ in increasing levels of the Ya-type subunits, although it was not found to be as potent an inducer of the other GST subunits, including Yc2. In addition to induction of GST, EQ caused a substantial increase in the hepatic content of AFB1-AR. Both BHA and BHT were also able to induce this enzyme but, by contrast, PB was found to be a poor inducer of AFB1-AR. AFB1, 3-MC and clofibrate were unable to serve as inducers of this reductase. The presence of Alpha-class GST, including the Yc2 subunit, was examined in various rat tissues. Constitutive expression of Yc2 was found in the epididymis at levels comparable with that observed in the liver from EQ-treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of aflatoxin B1-metabolizing aldehyde reductase and glutathione S-transferase by chemoprotectors. 819 22

A number of xenobiotics, including the synthetic antioxidant ethoxyquin, inhibit aflatoxin B1 (AFB1)-induced hepatocarcinogenesis in the rat. Two detoxification enzymes that mediate ethoxyquin-induced chemoprotection against AFB1 have been identified by protein purification: a glutathione S-transferase (GST) Yc2 subunit with at least 100-fold greater activity towards AFB1-8,9-epoxide than previously studied transferases, and a unique aldehyde reductase with activity towards the dialdehydic form of AFB1-8,9-dihydrodiol. Molecular cloning has revealed that the Yc2 subunit is a class alpha GST and that the aflatoxin-metabolizing aldehyde reductase (AFAR) is a distant member of the aldo-keto reductase superfamily. Enzyme assay and western blotting have shown that many chemoprotectors, such as ethoxyquin, butylated hydroxyanisole, butylated hydroxytoluene, oltipraz and indole-3-carbinol, that inhibit AFB1-mediated hepatocarcinogenesis induce both GST Yc2 and AFAR. However, western blotting suggests that these enzymes are not always coordinately regulated, as treatment with phenobarbital and beta-naphthoflavone results in differences in the relative increase in hepatic GST Yc2 and AFAR. These findings indicate that GST Yc2 and AFAR represent important resistance mechanisms against AFB1 in the rat. This conclusion is supported by the observation that GST Yc2 and AFAR are overexpressed in rat liver preneoplastic nodules, which display pleiotropic drug resistance.
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PMID:Regulation of glutathione S-transferases and aldehyde reductase by chemoprotectors: studies of mechanisms responsible for inducible resistance to aflatoxin B1. 892 30

Previously, we proposed that reactive aldehydic products generated from lipid peroxidation might be the deleterious cause of mitochondrial dysfunction during aging. Our present study focuses on the roles that aging and dietary restriction (DR) play in the elimination of 4-hydroxynonenal (HNE) in rat liver by exploring three enzymatic systems: aldehyde dehydrogenase (ALDH), glutathione S-transferase (GST), and alcohol dehydrogenase (ADH). Results show that the main pathways of HNE elimination in mitochondria are through ALDH-catalyzed oxidation, and the GST-catalyzed conjugation of HNE. Findings also show that age reduces both ALDH and GST activities; mitochondrial HNE oxidation by ALDH declines at 18 and 24 months of age, and the glutathione conjugation of HNE reduces at 24 months of age. However, these enzymatic processes were found to be well-preserved in DR animals throughout their life span, supporting the evidence of less HNE accumulation in the membranes of restricted rats. These findings are consistent with our earlier proposal that indicates an age-associated decrease in mitochondrial detoxification as a major underlying process for malondialdehyde and lipofuscin accumulation in older animals. They also indicate that the prevention of the age-associated decrease in aldehyde detoxification by DR may be an important mechanism underlying enhanced aldehyde elimination, thus minimizing the functional deterioration observed in mitochondria of old animals.
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PMID:Detoxification of reactive aldehydes in mitochondria: effects of age and dietary restriction. 895 35

A range of potential chemoprotective agents, most of them natural dietary constituents, has been examined for ability to modulate both phase I (cytochrome P450 1A1, 1A2, 2B1/2, 2C11, 2E1, 3A, 4A) and phase II drug metabolizing enzymes (glutathione S-transferases, in particular subunits Yc2 and P, aflatoxin B1-aldehyde reductase and quinone reductase) in rat liver. In addition to assays of total enzyme activity and Western blots for individual isozymes, the ability of microsomes to metabolize aflatoxin B1, and of cytosols to conjugate aflatoxin B1 (AFB1)-epoxide to GSH and to produce AFB1-dialcohol, were measured. Induction of gamma-glutamyl transpeptidase activity was examined by histochemistry. Differing patterns of induction were observed, reflecting differences in the control of expression of the individual enzymes studied. Of the compounds examined, butylated hydroxytoluene, ethoxyquin, indole-3-carbinol and phenethyl isothiocyanate were the most potent bifunctional agents (inducing both phase I and II activities). Oltipraz, while only weakly inducing CYP1A2 and 2B1/2, was a potent inducer of phase II enzymes. Caffeic acid, garlic oil, sinigrin and propyl gallate all showed some ability to induce phase II enzymes. 4-Methyl catechol, alpha-tocopherol and red wine decreased certain phase I enzyme activities, while inducing total GST activity. Butylated hydroxytoluene, ethoxyquin, garlic oil and indole-3-carbinol induced gamma glutamyltranspeptidase in periportal hepatocytes. Particularly because of their ability to induce the detoxifying activities of glutathione S-transferase Yc2 and aldehyde reductase, butylated hydroxytoluene, ethoxyquin, indole-3-carbinol, oltipraz, phenethyl isothiocyanate and sinigrin will be effective blocking agents in rodents, if administered prior to AFB1. While these studies indicate the relative contributions of phase I and II metabolism in the overall protective effect in rat, care should be taken that a similar balance is achieved in man, and that relevant enzymes or iso forms are induced.
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PMID:Mechanism of action of dietary chemoprotective agents in rat liver: induction of phase I and II drug metabolizing enzymes and aflatoxin B1 metabolism. 932 68

Fischer 344 rats fed on a diet that is deficient in selenium are more resistant to the hepatocarcinogen aflatoxin B1 (AFB1) than those fed on a selenium-sufficient diet. Hepatic cytosol from either selenium-deficient Fischer 344 rats or Hooded Lister rats possesses a marked increase in both reductase activity toward AFB1-dialdehyde and glutathione S-transferase (GST) activity toward AFB(1)-8,9-epoxide than hepatic cytosol from selenium-sufficient rats. The elevation in hepatic AFB1-aldehyde reductase (AFAR) activity in selenium-deficient animals is accompanied by an increase of 11- and 15-fold in the levels of AFAR protein in liver cytosol from Fischer 344 and Hooded Lister rats, respectively. The amount of AFAR protein in selenium-sufficient and -deficient Fischer rats was modulated by treatment with N-acetylcysteine; this antioxidant reduced basal expression of AFAR but did not modulate the relative overexpression of AFAR during selenium deficiency. The enhanced capacity to conjugate glutathione with AFB(1)-8,9-epoxide in selenium-deficient livers from Fischer 344 and Hooded Lister rats is associated with a 5- and 7-fold increase, respectively, in the hepatic levels of the AFB1-metabolizing alpha-class GSTA5 subunit. The elevated levels of AFAR and GSTA5 protein in the selenium-deficient animals coincided with increases in the steady-state levels of their mRNAs. In selenium-deficient Fischer 344 rats, AFAR and GSTA5 were both found to be expressed throughout the centrilobular and midzonal areas of the liver lobule but were essentially absent from periportal hepatocytes. The effect of selenium insufficiency is pleiotropic, and it was also noted that the theta-class GSTT1 is overexpressed 3- and 10-fold in livers of selenium-deficient Hooded Lister and Fischer 344 rats. Inasmuch as GSTT1 is responsible for the metabolic activation of dihaloalkanes, selenium deficiency may increase the susceptibility of rats to mutagens such as dichloromethane.
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PMID:Protection conferred by selenium deficiency against aflatoxin B1 in the rat is associated with the hepatic expression of an aldo-keto reductase and a glutathione S-transferase subunit that metabolize the mycotoxin. 933 Oct 86


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