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:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The induction of a variety of drug-metabolizing enzymes by polychlorinated biphenyl (PCB) congeners that elicit a 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD)-type hepatic pleiotropic response, including 2,3,3',4,4'-pentachlorobiphenyl (BZ 105), 2,3',4,4',5-pentachlorobiphenyl (BZ 118), 2,3,3',4,4',5-hexachlorobiphenyl (BZ 156), and 3,3',4,4',5,5'-hexachlorobiphenyl (BZ 169) was examined. Following dietary exposure to the individual congeners for 5 days, livers were removed and catalytic assays for cytochrome P450 (CYP) isozymes 1A1 and 1A2 were performed. Additionally, total cellular RNA coding for hepatic drug-metabolizing genes (CYP 1A1, CYP 1A2, microsomal epoxide hydrolase, glutathione S-transferase [GST] Ya/Yc, and the TCDD-inducible isozyme of aldehyde dehydrogenase [ALDH] was quantified. 3-Methylcholanthrene (MC), TCDD, or BZ 156 (32 ppm) caused nearly maximal induction of the CYP 1A proteins but lower induction of the other genes. When the dose-response curves for induction of various drug-metabolizing genes (CYP 1A1 and 1A2, microsomal epoxide hydrolase, the GST Ya/Yc subfamily and ALDH) were examined, a spectrum of ED50s (half-maximal inductions) was observed. While CYP 1A2 exhibited an ED50 of 1.7 ppm, the induction of ALDH was shifted far to the right (ED50 > 11 ppm). Thus, different genes in a single tissue may display different dose-response characteristics. The potency (extent of induction of CYP 1A1 activity resulting from a given dietary dose) was BZ 169 >> BZ 156 > BZ 118 > BZ 105. In contrast, the potencies of the four congeners for CYP 1A1 induction were nearly equivalent when related to hepatic PCB burden, apparently due to the preferential accumulation in the liver of BZs 169 and 156 following low-level administration in the diet.
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PMID:Relative potencies of induction of hepatic drug-metabolizing enzyme genes by individual PCB congeners. 778 61

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 development of drug resistance is an important factor contributing to failure of chemotherapy in cancer patients. Cyclophosphamide (CP) is a cytostatic drug widely used in the treatment of haematological malignancies and solid tumours. Because CP requires bioactivation to become cytotoxic, an in vivo approach was chosen to generate a subline of the Brown Norway rat acute myelocytic leukaemia (BNML/CPR) highly resistant to CP to serve as a model to investigate the molecular mechanism(s) of cyclophosphamide resistance. The role of the CP-detoxifying enzyme aldehyde dehydrogenase (ALDH) in the molecular mechanism of CP resistance in this subline of the BNML has been investigated. Compared to the parent BNML cell line, the BNML/CPR cell line displayed an approximately 6-fold higher level of ALDH enzyme activity. Pretreatment of leukaemic rats with the ALDH inhibitor disulfiram resulted in a restoration of CP sensitivity of animals carrying the BNML/CPR cells. Furthermore, in vitro incubation of BNML/CPR cells with disulfiram prior to incubation with the activated CP derivative mafosfamide resulted in an extra 2-3 log cell kill as indicated by the survival time of rats which were injected with disulfiram pretreated BNML/CPR cells compared to non-pretreated BNML/CPR cells. Data on the glutathione S-transferases (GSTs) isozyme profiles of cytoplasmic liver and spleen extracts of BNML- and BNML/CPR-carrying leukaemic rats indicated that the total GST enzyme amount was lower in BNML/CPR cells than in parent BNML cells. Furthermore, the BNML/CPR subline proved to be sensitive to phosphoramide mustard, both in vivo and in vitro.
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PMID:Aldehyde dehydrogenase involvement in a variant of the brown Norway rat acute myelocytic leukaemia (BNML) that acquired cyclophosphamide resistance in vivo. 785 14

High-level cytosolic class-3 aldehyde dehydrogenase (ALDH-3)-mediated oxazaphosphorine-specific resistance (> 35-fold as judged by the concentrations of mafosfamide required to effect a 90% cell-kill) was induced in cultured human breast adenocarcinoma MCF-7/0 cells by growing them in the presence of 30 microM catechol for 5 days. Resistance was transient in that cellular sensitivity to mafosfamide was fully restored after only a few days when the inducing agent was removed from the culture medium. The operative enzyme was identified as a type-1 ALDH-3. Cellular levels of glutathione S-transferase and DT-diaphorase activities, but not of cytochrome P450 IA1 activity, were also elevated. Other phenolic antioxidants, e.g. hydroquinone and 2,6-di-tert-butyl-4-hydroxytoluene, also induced ALDH-3 activity when MCF-7/0 cells were cultured in their presence. Thus, the increased expression of a type-1 ALDH-3 and the other enzymes induced by these agents was most probably the result of transcriptional activation of the relevant genes via antioxidant responsive elements present in their 5'-flanking regions. Cellular levels of ALDH-3 activity were also increased when a number of other human tumor cell lines, e.g. breast adenocarcinoma MDA-MB-231, breast carcinoma T-47D and colon carcinoma HCT 116b, were cultured in the presence of catechol. These findings should be viewed as greatly expanding the number of recognized environmental and dietary agents that can potentially negatively influence the sensitivity of tumor cells to cyclophosphamide and other oxazaphosphorines.
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PMID:Phenolic antioxidant-induced overexpression of class-3 aldehyde dehydrogenase and oxazaphosphorine-specific resistance. 788 82

The murine aromatic hydrocarbon ([Ah]) gene battery consists of at least six genes that code for two functionalizing (Phase I) enzymes and four non-functionalizing (Phase II) enzymes. These enzymes are induced by compounds such as aromatic hydrocarbons and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) that bind to the cytosolic Ah receptor protein. Studies in rodents indicate that certain enzymes of this battery, namely cytochrome P4501A1 (CYP1A1), UDP-glucuronosyltransferase (UGT1*06) and NAD(P)H: quinone acceptor oxidoreductase (NMO1) are induced by the synthetic antioxidant 5,10-dihydroindeno[1,2-b]indole (DHII). The induction of [Ah] gene battery enzymes and the levels of reduced glutathione (GSH) were examined in mouse Hepa-1c1c7 hepatoma wild-type cells (wt), a CYP1A1 metabolism-deficient mutant (c37) and an Ah receptor nuclear translocation-defective mutant (c4). DHII and TCDD increased the activities of ethoxyresorufin O-deethylase, an indicator of CYP1A1 activity, as well as NMO1, UGT1*06, cytosolic aldehyde dehydrogenase class 3 and glutathione S-transferase form A1 in wt cells, but had little or no induction effect in c37 or c4 cells. DHII and TCDD differed in their effects on GSH levels; while DHII increased GSH levels 3-fold in wt, but not at all in c37 or c4 cells, TCDD had no effect on GSH levels in any cell type. However, GSH levels were enhanced in both wt and c4 cells by tert-butyl hydroquinone (TBHQ). L-Buthionine S,R-sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase, prevented DHII-induced increases in wt cell GSH. The increase in GSH levels occurred after 8 h, while the induction of enzymes occurred within 4 h. The induction of the higher GSH levels in wt cells by DHII and TBHQ correlated with increases in intracellular levels of the GSH precursor thiol cysteine, as well as with increased activities of gamma-glutamylcysteine synthetase, the rate-limiting enzyme of GSH synthesis. However, TBHQ-mediated GSH increases in c4 cells were accompanied by increased gamma-glutamylcysteine synthetase activity with no change in intracellular cysteine concentration. The results suggest that DHII induction of [Ah] gene battery enzymes requires a functional Ah receptor, but not the functional gene product CYP1A1. Furthermore, metabolism, possibly via CYP1A1, appears to be required for DHII to enhance intracellular levels of cysteine and GCS activity that result in higher GSH levels.
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PMID:Regulation of [Ah] gene battery enzymes and glutathione levels by 5,10-dihydroindeno[1,2-b]indole in mouse hepatoma cell lines. 795 76

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

Biochemical and histochemical studies were conducted in aflatoxin B1-induced liver tumors in adult rainbow trout. Specific activities of the phase I enzymes, ethoxyresorufin-O-deethylase (EROD), microsomal and cytosolic epoxide hydrolase (mEH and cEH), aldehyde dehydrogenase (ALDH) and DT-diaphorase, and the phase II enzymes, gamma-glutamyltransferase (gamma-GT), glutathione transferase (GST) and uridine diphosphoglucuronyl transferase (UDPGT) were measured. Cryostat sections of tumor and surrounding liver from the same cohorts were analyzed immunohistochemically for cytochrome P450IA1 and histochemically for ALDH (benzaldehyde and hexanal), DT-diaphorase, gamma-GT and uridine diphosphoglucuronyl dehydrogenase (UDPGdH). In tumor tissues, the largest biochemical changes were found with benzaldehyde dehydrogenase, where activity increased from undetectable levels to 7.4 nmol/min/mg protein, and gamma-GT, where activity increased 12-fold over controls. Increases in other enzymes ranged from 1.26 to 2.84 times that of control liver, except EROD, which decreased, and cEH and mEH, which were unchanged. Histochemical analyses showed the induction of ALDH, gamma-GT, DT-diaphorase and UDPGdH, and the depression of cytochrome P450IA1 in hepatic neoplasms. In addition, marker enzyme histochemistry of neoplasms revealed heterogeneous populations of hepatocytes and absence of necrotic areas.
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PMID:Biochemical and histochemical properties of hepatic tumors of rainbow trout, Oncorhynchus mykiss. 809 46

The class-3 aldehyde dehydrogenase that is overexpressed (> 100-fold) in human breast adenocarcinoma MCF-7/0 cells made resistant (> 30-fold as judged by LC90s) to oxazaphosphorines, such as mafosfamide, by growing them in the presence of polycyclic aromatic hydrocarbons, e.g., methylcholanthrene (3 microM for 5 days), was isolated and characterized. Its physical and catalytic properties were identical to those of the prototypical human stomach mucosa cytosolic class-3 aldehyde dehydrogenase, type-1 ALDH-3, except that it catalyzed, though not very rapidly, the oxidation of aldophosphamide, whereas the stomach mucosa enzyme essentially did not; hence, it was judged to be a slight variant of the prototypical enzyme. Carcinogens that are not ligands for the Ah receptor, barbiturates known to induce hepatic cytochrome P450s, steroid hormones, an antiestrogen, and oxazaphosphorines did not induce the enzyme or the largely oxazaphosphorine-specific acquired resistance. Whereas methylcholanthrene induced (a) resistance to mafosfamide and (b) class-3 aldehyde dehydrogenase activity, as well as glutathione S-transferase and DT-diaphorase activities, in the estrogen receptor-positive MCF-7/0 cells, it did not do so in two other human breast adenocarcinoma cell lines, MDA-MB-231 and SK-BR-3, each of which is estrogen receptor negative. Expression of the class-3 aldehyde dehydrogenase and the loss of sensitivity to mafosfamide by polycyclic aromatic hydrocarbon-treated MCF-7/0 cells were transient; each returned to essentially basal levels within 15 days when the polycyclic aromatic hydrocarbon was removed from the culture medium. Insensitivity to the oxazaphosphorines on the part of polycyclic aromatic hydrocarbon-treated MCF-7/0 cells was not observed when exposure to mafosfamide (30 min) was in the presence of benzaldehyde or octanal, each a relatively good substrate for cytosolic class-3 aldehyde dehydrogenases, whereas it was retained when exposure to mafosfamide was in the presence of acetaldehyde, a relatively poor substrate for these enzymes. These observations demonstrate that ligands for the Ah receptor can induce a transient, largely oxazaphosphorine-specific, acquired cellular resistance, and they are consistent with the notion that elevated levels of a cytosolic class-3 aldehyde dehydrogenase nearly identical to the prototypical type-1 class-3 aldehyde dehydrogenase expressed by human stomach mucosa account for the Ah receptor ligand-induced oxazaphosphorine-specific acquired resistance, most probably by catalyzing the detoxification of aldophosphamide.
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PMID:Identification of a methylcholanthrene-induced aldehyde dehydrogenase in a human breast adenocarcinoma cell line exhibiting oxazaphosphorine-specific acquired resistance. 817 25

The major proteins (crystallins) of the transparent, refractive eye lens of vertebrates are a surprisingly diverse group of multifunctional proteins. A number of lens crystallins display taxon-specificity. In general, vertebrate crystallins have been recruited from stress-protective proteins (i.e. the small heat-shock proteins) and a number of metabolic enzymes by a gene-sharing mechanism. Despite the existence of refractive lenses in the complex and compound eyes of many invertebrates, relatively little is known about their crystallins. Here we review for the first time the state of knowledge of invertebrate crystallins. The major cephalopod (squid, octopus, and cuttlefish) crystallins (S-crystallins) have, like vertebrate crystallins, been recruited from a stress protective metabolic enzyme, glutathione S-transferase. The presence of overlapping AP-1 and antioxidant responsive-like sequences that appear functional in transfected vertebrate cells suggest that the recruitment of glutathione S-transferase to S-crystallins involved response to oxidative stress. Cephalopods also have at least two taxon-specific crystallins: omega-crystallin, related to aldehyde dehydrogenase, and omega-crystallin, related to a superfamily of lipid-binding proteins. L-crystallin (probably identical to O-crystallin) is the major protein of the lens of the squid photophore, a specialized structure for emitting light. The use of L/omega-crystallin in the ectodermal lens of the eye and the mesodermal lens of the photophore of the squid contrasts with the recruitment of different crystallins in the ectodermal lenses of the eye and photophore of fish. S-and omega-crystallins appear to be lens-specific (some S-crystallins are also expressed in cornea) and, except for one S-crystallin polypeptide (SL11/Lops4; possibly a molecular fossil), lack enzymatic activity. The S-crystallins (except SL11/Lops4) contain a variable peptide that has been inserted by exon shuffling. The only other invertebrate crystallins that have been examined are in one marine gastropod (Aplysia, a sea hare), in jellyfish and in the compound eyes of some arthropods; all are different and novel proteins. Drosocrystallin is one of three calcium binding taxon-specific crystallins found selectively in the acellular corneal lens of Drosophila, while antigen 3G6 is a highly conserved protein present in the ommatidial crystallin cone and central nervous system of numerous arthropods. Cubomedusan jellyfish have three novel crystallin families (the J-crystallins); the J1-crystallins are encoded in three very similar intronless genes with markedly different 5' flanking sequences despite their almost identical encoded proteins and high lens expression. The numerous refractive structures that have evolved in the eyes of invertebrates contrast markedly with the limited information on their protein composition, making this field as exciting as it is underdeveloped. The similar requirement of Pax-6 (and possibly other common transcription factors) for eye development as well as the diversity, taxon-specificity and recruitment of stress-protective enzymes as crystallins suggest that borrowing multifunctional proteins for refraction by a gene sharing strategy may have occurred in invertebrates as did in vertebrates.
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PMID:Lens crystallins of invertebrates--diversity and recruitment from detoxification enzymes and novel proteins. 865 88

The drug disulfiram (DSF, Antabuse) has been used in the therapy of alcohol abuse. It is a potent inhibitor of aldehyde dehydrogenase. Its reduced form, diethyldithiocarbamate (DDTC), and further metabolites show similar activities. DSF and DDTC have also been widely used to inhibit mixed-function oxidases. In this study, the reversible inhibition and time-dependent inactivation of the major rat and human glutathione S-transferase (GST) isoenzymes by DSF and DDTC was investigated. Reversible inhibition, using 1-chloro-2,4-dinitrobenzene as substrate for the GST alpha-, mu-, and pi-class, expressed as I50 (in microM), ranged from 5-18 (human A1-1), 43-57 (rat 4-4) and 66-83 (rat 1-1), for both DSF and DDTC. The I50 for rat GST theta, using 1,2-epoxy-3-(p-nitrophenoxy)-propane as substrate, was 350 microM for DDTC. The other GSTs were significantly less sensitive to inhibition. The major part of reversible inhibition by DSF was shown to be due to DDTC, formed rapidly upon reduction of DSF by the glutathione (GSH) present in the assay to measure GST activity. The oxidized GSH formed upon reduction of DSF might also have made a minor contribution to reversible inhibition. The rat and human pi-class was, by far, the most sensitive class for time-dependent inactivation by DSF, but no such inactivation was observed for any of the GSTs by DDTC. Moderate susceptibility to inactivation by DSF of all the other GSTs was observed, except for human A2-2, which does not possess a cysteine residue. Consistent with the assumption that a thiol residue is involved in this inactivation, a significant part of the activity could be restored by treatment of the inactivated GST with GSH or dithiotreitol.
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PMID:In vitro inhibition of rat and human glutathione S-transferase isoenzymes by disulfiram and diethyldithiocarbamate. 869 43


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