Polymorphism- and Species-Dependent Inactivation of Glutathione Transferase Zeta by Dichloroacetate

Tzeng, Huey-Fen; Blackburn, Anneke C.; Board, Philip G.; Anders, M. W.

doi:10.1021/tx990175q

Cited by 85 publications

(100 citation statements)

References 31 publications

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“…Sections from different tissues, notably liver, brain, and testis, of rats given DCA showed sparse staining for GSTZ1-1, whereas the staining on sections from rats given CFA was similar to that of untreated rats (data not shown). These data indicate that DCA reduced the amount of immunoreactive GSTZ1-1 in hepatic and extra-hepatic tissues and corroborate the observations showing that DCA-inactivated GSTZ1-1 is degraded (Anderson et al, 1999) and that CFA is a poor inactivator of GSTZ1-1 (Tzeng et al, 2000).…”

Section: Tissuessupporting

confidence: 89%

“…The limited effects of DCA on GSTZ1-1 activities in extrahepatic tissue may be associated with the much lower turnover of DCA in these tissues compared with the rates in the liver where inactivation is rapid (Anderson et al, 1999;Tzeng et al, 2000). Given that MA turnover in extrahepatic tissues was not significantly different from in DCA-treated rats compared with control rats, it is possible that other GSTs also catalyze the isomerization of MA to FA, but DCA is not a substrate for GSTA, GSTM, GSTP, and GSTT (W. B. Anderson and M. W. Anders, unpublished observations).…”

Section: Tissue-dependent Expression and Activities Of Gstz1-1mentioning

confidence: 99%

“…Studies on the biotransformation of DCA by GSTZ1-1 show that DCA is a mechanism-based inactivator of GSTZ1-1 (Tzeng et al, 2000). Moreover, GSTZ1-1 activities and immunoreactive GSTZ1-1 protein concentrations are reduced in hepatic cytosolic fractions from rats given DCA for 5 days (Anderson et al, 1999).…”

Section: Introductionmentioning

confidence: 98%

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Immunohistochemical Localization and Activity of Glutathione Transferase Zeta (GSTZ1–1) in Rat Tissues

Lantum

Baggs²,

Krenitsky³

et al. 2002

Drug Metab Dispos

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ABSTRACT:Glutathione transferase zeta (GSTZ1-1) catalyzes the biotransformation of a range of ␣-haloacids, including dichloroacetic acid (DCA), and the penultimate step in the tyrosine degradation pathway. DCA is a rodent carcinogen and a common drinking water contaminant. DCA also causes multiorgan toxicity in rodents and dogs. The objective of this study was to determine the expression and activities of GSTZ1-1 in rat tissues with maleylacetone and chlorofluoroacetic acid as substrates. GSTZ1-1 protein was detected in most tissues by immunoblot analysis after immunoprecipitation of GSTZ1-1 and by immunohistochemical analysis; intense staining was observed in the liver, testis, and prostate; moderate staining was observed in the brain, heart, pancreatic islets, adrenal medulla, and the epithelial lining of the gastrointestinal tract, airways, and bladder; and sparse staining was observed in the renal juxtaglomerular regions, skeletal muscle, and peripheral nerve tissue. These patterns of expression corresponded to GSTZ1-1 activities in the different tissues with maleylacetone and chlorofluoroacetic acid as substrates. Specific activities ranged from 258 ؎ 17 (liver) to 1.1 ؎ 0.4 (muscle) nmol/min/mg of protein with maleylacetone as substrate and from 4.6 ؎ 0.89 (liver) to 0.09 ؎ 0.01 (kidney) nmol/min/mg of protein with chlorofluoroacetic acid as substrate. Rats given DCA had reduced amounts of immunoreactive GSTZ1-1 protein and activities of GSTZ1-1 in most tissues, especially in the liver. These findings indicate that the DCA-induced inactivation of GSTZ1-1 in different tissues may result in multiorgan disorders that may be associated with perturbed tyrosine metabolism.Glutathione transferases (GST 1 ) are a multigene family of phase II drug-metabolizing enzymes that catalyze the conjugation of glutathione with a range of endogenous and exogenous substrates (Armstrong, 1997;Salinas and Wong, 1999). Soluble and membrane-bound GSTs are expressed in many tissues, and soluble GSTs constitute 1 to 5% of total cytosolic protein (Morgenstern et al., 1984;Sundberg et al., 1993;Rowe et al., 1997). Activities with model substrates and the subcellular localization of GSTA, GSTM, GSTP, GSTT, and GSTO class GSTs and of microsomal GST1 have been previously characterized (Meyer et al., 1991;Hiratsuka et al., 1994;Mannervik and Widersten, 1995;Armstrong, 1997;Otieno et al., 1997;Yin et al., 2001).The expression of GSTs is regulated pre-and post-translationally in a tissue-specific manner resulting in protein products that differ quantitatively in different tissues (Tu et al., 1983;Rozell et al., 1993;Rowe et al., 1997). Testes express the highest amount of total GST protein per milligram cytosolic protein followed by the liver, brain, pancreas, adrenals, heart, and lung (DePierre and Morgenstern, 1983;Listowsky et al., 1998). Major GST-expressing tissues are the principal sites for drug and chemical metabolism indicative of the role of GSTs in the biotransformation of xenobiotics (Pabst et al., 1973;Armstrong, 1997). Studies...

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Section: Tissuessupporting

confidence: 89%

Section: Tissue-dependent Expression and Activities Of Gstz1-1mentioning

confidence: 99%

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Immunohistochemical Localization and Activity of Glutathione Transferase Zeta (GSTZ1–1) in Rat Tissues

Lantum

Baggs²,

Krenitsky³

et al. 2002

Drug Metab Dispos

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“…Dehalogenase Activity with DCA as Co-substrate-Enzyme activity was measured spectrophotometrically continuously at 340 nm and 37°C using a lactate dehydrogenase/NADH-coupled assay (20). The standard assay mixture (1-ml final volume) contained phosphate/acetate/borate buffer (50:50:50), pH 7.0, 1 mM EDTA, 1 mM GSH (10 mM with the C16A mutant), 1 mM DCA (10 mM with the C16A mutant), 0.2 mM NADH, 2 units of lactate dehydrogenase, and catalytic amounts of GSTZ1c-1c or C16A mutant enzymes.…”

Section: Methodsmentioning

confidence: 99%

“…The covalent bond involves one Cys 16 per dimer and induces a complete enzyme inactivation (19). This reaction only occurs in the presence of GSH as shown by Tzeng and co-workers (20). In an attempt to study the noncovalent interaction of the enzyme with DCA, we analyzed the UV spectral perturbation due to the co-substrate binding.…”

Section: Figmentioning

confidence: 96%

Binding and Kinetic Mechanisms of the Zeta Class Glutathione Transferase

Ricci

Turella

Maria

et al. 2004

Journal of Biological Chemistry

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The Zeta class of glutathione transferases (GSTs) has only recently been discovered and hence has been poorly characterized. Here we investigate the substrate binding and kinetic mechanisms of the human Zeta class GSTZ1c-1c by means of pre-steady state and steady-state experiments and site-directed mutagenesis. Binding of GSH occurs at a very low rate compared with that observed for the more recently evolved GSTs (Alpha, Mu, and Pi classes). Moreover, the single step binding mechanism observed in this enzyme is reminiscent of that found for the Theta class enzyme, whereas the Alpha, Mu, and Pi classes have adopted a multistep binding mechanism. Replacement of Cys 16 with Ala increases the rate of GSH release from the active site causing a 10-fold decrease of affinity toward GSH. Cys 16 also plays a crucial role in co-substrate binding; the mutant enzyme is unable to bind the carcinogenic substrate dichloroacetic acid in the absence of GSH. However, both substrate binding and GSH activation are not rate-limiting in catalysis. A peculiarity of the hGSTZ1c-1c is the half-site activation of bound GSH. This suggests a primitive monomer-monomer interaction that, in the recently diverged GSTP1-1, gives rise to a sophisticated cooperative mechanism that preserves the catalytic efficiency of this GST under stress conditions.

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Dichloressigsäure und ihre Salze [MAK Value Documentation in German language, 2010]

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Gesundheitsschädliche Arbeitsstoffe , 49. Lieferung, Ausgabe 2010 Der Artikel enthält folgende Kapitel: Allgemeiner Wirkungscharakter Wirkungsmechanismus Toxikokinetik und Metabolismus Aufnahme, Verteilung, Ausscheidung Metabolismus Erfahrungen beim Menschen Tierexperimentelle Befunde und In‐vitro‐Untersuchungen Akute Toxizität Subakute, subchronische und chronische Toxizität Wirkung auf Haut und Schleimhäute Allergene Wirkung Reproduktionstoxizität Genotoxizität Kanzerogenität Bewertung Anhang

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Polymorphism- and Species-Dependent Inactivation of Glutathione Transferase Zeta by Dichloroacetate

Cited by 85 publications

References 31 publications

Immunohistochemical Localization and Activity of Glutathione Transferase Zeta (GSTZ1–1) in Rat Tissues

Immunohistochemical Localization and Activity of Glutathione Transferase Zeta (GSTZ1–1) in Rat Tissues

Binding and Kinetic Mechanisms of the Zeta Class Glutathione Transferase

Dichloressigsäure und ihre Salze [MAK Value Documentation in German language, 2010]

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