Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies of others have shown that class 3 aldehyde dehydrogenase is a major component of the epithelial cells of the mammalian cornea. Here we demonstrate by peptide sequencing that other major proteins of the corneal epithelium are also identical or related to enzymes in the human, mouse, kangaroo, chicken, and squid. Aldehyde dehydrogenase class 3 was found to be the major protein of human, mouse, and kangaroo corneal epithelial cells. Peptidyl prolyl cis-trans isomerase (cyclophilin) or a homologue thereof is strikingly abundant in the corneal epithelial cells of chicken, but not mammals, and appears to be absent from the cornea of squid. By contrast, enolase or its homologue is relatively abundant in both the mammalian and chicken corneal epithelial cells. In some instances, abundant enzymes are common to cornea and lens in the same species--for example, arginino-succinate lyase/delta 1-crystallin in the chicken and glutathione S-transferase-like protein in the squid; in other cases, the abundant proteins in the cornea have not been found as lens crystallins in any species--for example, aldehyde dehydrogenase class 3 and cyclophilin. These data suggest that enzymes and certain enzyme-crystallins have been recruited as major corneal proteins in a taxon-specific manner and may serve structural rather than, or as well as, enzymatic roles in corneal epithelial cells.
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PMID:Taxon-specific recruitment of enzymes as major soluble proteins in the corneal epithelium of three mammals, chicken, and squid. 157 Mar 26

The study investigated the relationship between lipid peroxidation and enzyme inactivation in rat hepatic microsomes and whether prior inactivation of aldehyde dehydrogenase (ALDH) exacerbated inactivation of other enzymes. In microsomes incubated with 2.5 microM iron as ferric sulfate and 50 microM ascorbate, ALDH, glucose-6-phosphatase (G6Pase) and cytochrome P450 (Cyt-P450) levels decreased rapidly and concurrently with increased levels of thiobarbituric acid-reactive substances. Microsomal glutathione S-transferase and nicotinamide adenine dinucleotide phosphate-cytochrome c reductase were little affected during 1 hr of incubation. Addition of reduced glutathione partially protected and N,N'-diphenyl-p-phenylenediamine and butylated hydroxytoluene completely protected microsomes against inactivation of ALDH, G6Pase and Cyt-P450, as well as lipid peroxidation induced by iron and ascorbate. ALDH was more susceptible than G6Pase to inactivation by iron and ascorbate, and was thus an excellent marker for oxidative stress. Inhibition of ALDH by cyanamide injection of rats exacerbated the inactivation of G6Pase in microsomes incubated with 0.1 mM, but not 25 microM 4-hydroxynonenal (4-HN). 4-HN did not stimulate lipid peroxidation. Thus, 4-HN may play a minor role in microsomal enzyme inactivation. In contrast, lipid peroxyl radicals play an important role in microsomal enzyme inactivation, as evidenced by the prevention of both lipid peroxidation and enzyme inactivation by chain-breaking antioxidants.
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PMID:Glutathione and antioxidants protect microsomes against lipid peroxidation and enzyme inactivation. 160 2

Resistance to multiple chemotherapeutic agents is a common clinical problem in the treatment of cancer: such resistance may occur in primary therapy or be acquired during treatment. The most commonly used antineoplastic agents in the treatment of disseminated breast cancer are adriamycin, methotrexate and cyclophosphamide. Cell lines selected for resistance to adriamycin often develop cross-resistance to structurally dissimilar antineoplastic drugs with different mechanisms of cytotoxic action; this phenomenon has been called pleiotropic or multidrug resistance (MDR). In vitro models of MDR have shown that this type of resistance is accompanied by a decrease in cellular drug accumulation, mediated by the over-expression of a 170 kD plasma membrane glycoprotein referred to as P170. Glycoprotein P170 is an energy-dependent multidrug efflux pump, whose activity can be inhibited in vitro by a variety of agents including verapamil, quinidine and reserpine. P170 is over-expressed also in some human malignancies, and evidence exists about its role in examples of clinical resistance in vitro. Clinical trials using verapamil, a calcium channel blocker which selectively enhances drug cytotoxicity in MDR cell lines, have been prompted for leukemia and ovarian cancer. In addition other approaches are the subject of current preclinical investigations. Several observations as well the phenomenon of "atypical" MDR in cell lines which do not overexpress P170, suggest that also other factors are involved in multidrug resistance. Qualitative or quantitative changes in the activity of topoisomerases, protein kinase-related systems and glutathione S-transferase, may confer pleiotropic resistance. As the role of these genes and their regulation is clarified, they may also serve as useful targets for pharmacologic intervention in the treatment of drug-resistant human tumors. The mechanisms involved in resistance to methotrexate and cyclophosphamide are less studied, particularly in vivo samples. Methotrexate resistance is probably a complex multifactorial phenomenon; in some cases it is due to an increase in the expression of the drug target dihydrofolate reductase, often as a result of gene amplification, but in other cases a transport defect of the methotrexate or alterations of the activity of different enzymes have been reported. Cyclophosphamide (CP) resistance has been attributed to an increased activity of two different enzymes, glutathione S-transferase, also involved in MDR phenotype, and aldehyde dehydrogenase, which catalyzes inactivation of CP in non cytotoxic metabolites. This paper reviews the current state of our knowledge of chemo-resistance and the utility of available markers to identify potentially resistant tumors in vivo; the strategies that might be used to overcome this phenomenon are also described.
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PMID:Chemoresistance in breast tumors. 168 Jun 89

The time courses of induction of liver cytosolic aldehyde dehydrogenases using benzaldehyde and propionaldehyde as substrates and NADP and NAD as co-factors after i.p. and intragastric (i.g.) administration of 2-acetylaminofluorene (2-AAF), 20-methylcholanthrene (20-MC), beta-naphthoflavone (beta-NF) and benzo[alpha]pyrene (B[alpha]P) were investigated in male Wistar rats. 2-AAF did not induce the aldehyde dehydrogenase activities with any substrate:co-factor combination. The other three inducers all induced the oxidation of the aldehydes in a reversible manner. With an i.p. route of administration (one daily dose for four consecutive days) (20-MC) was the most potent inducer giving a 240-fold increase of benzaldehyde: NADP activity on the ninth day. beta-NF elevated the activity 20-fold with peak activity at day 7, while B[alpha]P gave maximal induction on day 5 with a 60-fold increase in activity over the corresponding value for normal liver. The i.g. administration resulted in a weaker but coordinated induction of activity with peak activity on the sixth day for the different inducers. The activity ratio benzaldehyde:NADP/propionaldehyde:NAD, 0.78 in normal rats, was altered in all induced states to a level close to 4. The interpretation of our work supports the hypothesis that the inducers in this respect use the same mechanisms of induction. The differences noted can be explained by variations in the exposure of the liver to the administered dose and/or by differences in receptor affinity. The inducibility of benzaldehyde:NADP aldehyde dehydrogenase in rat liver exceeds by orders of magnitude the ability of the same inducers to increase the amount of the activity of other drug metabolizing enzymes such as glutathione S-transferase, cytochrome P450 and cytochrome b5. The reversible, drug-dependent induction characterized in normal rat liver in this work differs entirely from the persistent constitutive elevation of the same enzymes in preneoplastic liver nodules.
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PMID:Kinetics of induction of cytosolic benzaldehyde: NADP and propionaldehyde: NAD aldehyde dehydrogenase activities in rat livers from male Wistar rats. 202 38

In the rat, a cytosolic isozyme of aldehyde dehydrogenase, designated ALDH-PB, can be induced in the liver by administration of phenobarbital (PB). ALDH-PB activity and mRNA are induced in Long-Evans rats that possess a responsive (R) allele but are not induced in homozygous nonresponsive rats (rr), although the rr genotype is competent to induce other PB-responsive mRNAs. ALDH-PB mRNA is expressed in the basal state (without PB administration) in hepatic tissue in both RR and rr genotypes. We report the complete nucleotide sequence of the rat ALDH-PB mRNA. The protein encoded by the ALDH-PB mRNA is 501 amino acids in length and has a predicted molecular mass of 54,540 daltons. The amino acid sequence predicted from the mRNA demonstrates a strong conservation between the rat ALDH-PB and the human cytosolic aldehyde dehydrogenase hALDH-1. We demonstrate the ALDH-PB, cytochrome P-450b, cytochrome P-450e, and glutathione S-transferase Ya subunit mRNA levels in the liver are altered noncoordinately by administration of PB in RR and rr genotypes. The strikingly different responses to PB administration between the various mRNA species in each of the genotypes suggest that the regulation of specific gene expression by PB may involve multiple pathways.
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PMID:Phenobarbital-inducible aldehyde dehydrogenase in the rat. cDNA sequence and regulation of the mRNA by phenobarbital in responsive rats. 275

Using the Solt-Farber hepatocarcinogenesis model, a large population of preneoplastic and neoplastic nodules were induced in male Fischer 344 rats. Total cellular polypeptides from normal liver and individual preneoplastic and neoplastic nodules were analyzed for both qualitative and quantitative changes using computer assisted high resolution two-dimensional electrophoresis. Approximately 800-1000 cytosolic and 1200-1400 membrane associated polypeptides were readily separated and detected using an ultrasensitive silver stain. The polypeptide patterns were remarkably similar for each tissue and only four qualitative polypeptide differences were noted. One cytosolic polypeptide, 6.8/57 (designated pl/Mr X 10(-3), and three membrane associated polypeptides, 6.25/41, 6.75/24, and 6.05/21, were expressed in both preneoplastic and neoplastic nodules but not in normal liver. No qualitative polypeptide differences were detected among the individual preneoplastic or individual neoplastic nodules or between preneoplastic and neoplastic nodules. Numerous quantitative changes in both known markers for hepatocarcinogenesis and in as yet unidentified polypeptides were noted. In particular, the Ya subunit of glutathione S-transferase B, the Yb subunit of glutathione S-transferase A, as well as the three isoelectric point variants of the Yp subunit of glutathione S-transferase P were increased 2-, 4-, and 7-fold, respectively, in preneoplastic and neoplastic nodules. Whereas DT-diaphorase was increased 2-3-fold in hyperplastic nodules as compared to normal liver, no differences in the expression of albumin were noted. Although no differences were observed in the expression of aldehyde dehydrogenase in preneoplastic and neoplastic nodules, polypeptide b (6.9/54) was shifted slightly toward the basic region in normal liver. alpha-Fetoprotein was not detected in either preneoplastic or neoplastic nodules. In addition to these changes in known markers, comparison of 500-800 cytosolic and 750-1000 membrane associated polypeptides showed that roughly 4-10% of the polypeptides were undergoing quantitative changes of at least 4-fold during these stages of hepatocarcinogenesis. Thirty (10 cytosolic and 20 membrane) polypeptides were significantly down-regulated while 22 (7 cytosolic and 15 membrane) polypeptides were up-regulated in both preneoplastic and neoplastic nodules. In all cases the direction and magnitude of change were the same in both preneoplastic and neoplastic nodules with the exception of three polypeptides.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sequential analysis of chemically induced hepatoma development in rats by two dimensional electrophoresis. 394 Feb 6

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

We examined the incidence of proliferative lesions, hyperplastic nodules and altered hepatic foci, in male F344 rat liver, to determine their preneoplastic potential during dichloroacetic acid (DCA)-induced hepatocarcinogenesis. Immunohistochemical and image analysis methods were used to detect the expression of 6 histochemical markers of neoplastic cells; p21 ras, p39 c-jun, p55 c-fos, aldehyde dehydrogenase (ALDH), glutathione s-transferase (GST-p), and alpha fetoprotein (AFP) during DCA-induced hepatocarcinogenesis. Our results were consistent with our previous data and suggested that the hyperplastic nodules, rather than altered hepatic foci, is a putative preneoplastic lesion during DCA-induced hepatocarcinogenesis in the male F344 rat.
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PMID:Immunohistochemical analysis of dichloroacetic acid (DCA)-induced hepatocarcinogenesis in male Fischer (F344) rats. 753 96

Induction of Phase II enzymes of the [Ah] gene battery by L-buthionine (S,R)-sulfoximine (BSO) and other agents was examined in mouse hepatoma Hepa-1c1c7 cells. BSO, a nonelectrophilic inhibitor of gamma-glutamylcysteine synthetase (GCS), is routinely used to examine the toxicological implications of GSH depletion. Exposure to BSO for 24 h produced a 75-85% depletion of GSH levels, proportional to the inhibition of GCS activity, as well as small increases in the UDP-glucuronosyltransferase (UGT, 60%) and glutathione transferase (GST, 30%) enzyme activities in Hepa-1 wild-type (wt) cells. However, for the NAD(P)H:menadione oxidoreductase (NMO1) and cytosolic aldehyde dehydrogenase class 3 (AHD4) enzyme activities, BSO produced larger increases (110% and 170%, respectively). The mechanisms of NMO1 and AHD4 induction were examined further. In Hepa-1 wt cells, NMO1 and AHD4 activities were increased by the aromatic hydrocarbon inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and by the electrophile tert-butylhydroquinone (tBHQ), known inducing agents for these enzymes. However, NMO1 and AHD4 were induced in Ah receptor nuclear translocation-defective mutant (c4) cells by BSO and tBHQ, but not by TCDD, suggesting that the induction by BSO and tBHQ is not Ah receptor-mediated. In wt cells, N-acetylcysteine produced a concentration-dependent increase in intracellular cysteine levels, but not GSH levels, in the absence or presence of BSO. Furthermore, N-acetylcysteine had no effect on NMO1 activity under any conditions examined, suggesting that GSH levels per se, rather than change in overall thiol status, might be mediating increased NMO1 activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enzyme induction by L-buthionine (S,R)-sulfoximine in cultured mouse hepatoma cells. 757 30

A number of genes under the control of the arylhydrocarbon (Ah) receptor were tested for the effects of glucocorticoids on their expression in cultured primary rat hepatocytes. Treatment of cultured hepatocytes with 1.0 microM dexamethasone potentiated the induction (2- to 3-fold) of cytochrome P4501A1, glutathione S-transferase Ya subunit (GSTYa), and UDP-glucuronosyltransferase gene expression by polycyclic aromatic hydrocarbons (PAH), whereas the glucocorticoid agonist suppressed PAH induction of NAD(P)H:quinone oxidoreductase (QOR) subunit and aldehyde dehydrogenase 3C gene expression by 60-80%. These results were seen at the level of enzyme activity for induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin and at the level of enzyme activity, protein, and specific mRNA for induction by 1,2-benzanthracene. Two of these rat genes, GSTYa and QOR are also induced by electrophilic agents, such as t-butylhydroquinone. In the presence of t-butylhydroquinone, dexamethasone caused a similar level of potentiation of GSTYa subunit expression and suppression of QOR subunit expression as was seen with the PAH, 1,2-benzanthracene. Studies using the glucocorticoid receptor antagonist, RU38486, demonstrated that the modulation of PAH induction by glucocorticoids of cytochrome P4501A1 and QOR activity is apparently dependent on action of the glucocorticoid receptor. These results suggest that the positive and negative changes observed are the result of specific alterations in the rates of transcription of these genes because of the action of the glucocorticoid receptor, thereby affecting regulation of GSTYa and QOR by both Ah receptor-dependent and independent mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of the Ah gene battery via Ah receptor-dependent and independent processes in cultured adult rat hepatocytes. 758 46


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