Glutathione Transferases—Structure and Catalytic Activit

Mannervik, Bengt; Danielson, U. Helena

doi:10.3109/10409238809088226

Cited by 1,736 publications

(1,115 citation statements)

References 183 publications

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“…GSTs are a family of isoenzymes with broad substrate specificity that catalyze the conjugation of the tripeptide GSH to many xenobiotics [13]. Conjugation to GSH improves the solubility of these substrates and may facilitate their removal from the cell by GS-X pumps.…”

Section: Introductionmentioning

confidence: 99%

“…Conjugation to GSH improves the solubility of these substrates and may facilitate their removal from the cell by GS-X pumps. In addition, GSTs have been suggested to serve as intracellular sinks and carrier proteins for certain hydrophobic and electrophilic molecules [13][14][15]. Increased cellular amounts of GST isoenzymes are associated with resistance against alkylating agents and doxorubicin [12].…”

Section: Introductionmentioning

confidence: 99%

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Transport of the glutathione conjugate of ethacrynic acid by the human multidrug resistance protein MRP

et al. 1996

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The multidrug resistance protein MRP has been shown to mediate the transport of glutathione S-conjugates across membranes. In this study we demonstrate that the glutathione S-conjugate of the diuretic drug ethacrynic acid, which is an efficient inhibitor of glutathione S-transferases, is a high-affinity substrate and inhibitor of the glutathione Sconjugate pump associated with MRP. This implies that ethacrynic acid may modulate drug resistance of tumor cells not only by inhibiting glutathione S-transferase activity, but also by inhibiting the export of drug conjugates from the cell by MRP.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transport of the glutathione conjugate of ethacrynic acid by the human multidrug resistance protein MRP

et al. 1996

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“…Glutathione S-transferases (GST,3 EC 2.5.1.18) are a family of isozymes that can catalyze the covalent addition of the tripeptide glutathione, present at 0.5-10 mM in mammalian cells (35), to a structurally diverse array of physiological and xenobiotic electrophiles (21,25,32,37,41,52,53). GSTs are ubiquitous in the animal and plant kingdoms (53), and Mannervik (32) has classified the mammalian cytosolic GSTs into three classes (Pi, Alpha, and Mu) based on structural, immunological, and enzymatic properties.…”

Section: Key Terms: Resistance To Carcinogens Reversion Of Transientmentioning

confidence: 99%

Section: Key Terms: Resistance To Carcinogens Reversion Of Transientmentioning

confidence: 99%

“…GSTs are ubiquitous in the animal and plant kingdoms (53), and Mannervik (32) has classified the mammalian cytosolic GSTs into three classes (Pi, Alpha, and Mu) based on structural, immunological, and enzymatic properties. Mammalian cytosolic GSTs constitute 1-10% of total cytosolic protein (21) and are composed of two subunits (23-28 kilodaltons each) (32) that dimerize by noncovalent interactions (51). As demonstrated with in vitro kinetic analyses, GSTs can conjugate glutathione to anticancer alkylating agents (2,3,9,49,59), sequester hydrophobic compounds by noncovalent (32) 1783-1788, 1991), based upon in vitro kinetic analyses, support our findings done in whole cells which show that the rat )I and a class GSTs catalyze the conjugation of GSH to monochlorobimane more efficiently than 71 class GSTs.…”

Section: Key Terms: Resistance To Carcinogens Reversion Of Transientmentioning

confidence: 99%

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Recombinant glutathione S‐transferase (GST) expressing cells purified by flow cytometry on the basis of a GST‐catalyzed intracellular conjugation of glutathione to monochlorobimane

et al. 1991

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COS cells transiently expressing glutathione S-transferase (GST) m, Ya, or Yb, (human Pi, rat Alpha or Mu, cytosolic classes) were purified by flow cytometry and used in colony-forming assays to show that GST confers cellular resistance to the carcinogen benzoblpyrene (*)-anti-diol epoxide (anti-BPDE). We developed a sorting technique to viably separate recombinant GST+ cells (20%) from the nonexpressing electroporated population (80%) on the basis of a GST-catalyzed intracellular conjugation of glutathione to the fluorescent labeling reagent monochlorobimane (mClB). The concentration of mClB, length of time cells are exposed to mClB, and activity of the expressed GST isozyme determined the degree to which recombinant GST+ cells fluoresced more intensely than controls. On-line reagent addition ensured that all cells were exposed to 25 p M mClB for 3035 s during transit before being analyzed for fluorescence intensity and sorted. The apparent K , for mClB of the endogenous COS cell GST-catalyzed intracellular reaction was 88 pM. Stained GST Ya+ or Yb,+ cells catalyzed the conjugation 2 or 5 times more effectively than GST n+ cells. Enzyme activity in cytosolic fractions prepared from sorted recombinant GST+ cells was 1.8 -+ 0.3-fold greater than that of the control (80 f 4 nmoYmin/mg protein). Upon a 5-fold purification of GST n+ cells in the electroporated population, resistance to anti-BPDE in colony-forming assays increased 5 times, from 1.1-fold (unsorted) to 1.5-fold (sorted) (P <0.001).Key terms: Resistance to carcinogens, reversion of transient expression, COS cells Glutathione S-transferases (GST,3 EC 2.5.1.18) are a family of isozymes that can catalyze the covalent addition of the tripeptide glutathione, present at 0.5-10 mM in mammalian cells (35), to a structurally diverse array of physiological and xenobiotic electrophiles (21,25,32,37,41,52,53). GSTs are ubiquitous in the animal and plant kingdoms (53), and Mannervik (32) has classified the mammalian cytosolic GSTs into three classes (Pi, Alpha, and Mu) based on structural, immunological, and enzymatic properties. Mammalian cytosolic GSTs constitute 1-10% of total cytosolic protein (21) and are composed of two subunits (23-28 kilodaltons each) (32) that dimerize by noncovalent interactions (51). As demonstrated with in vitro kinetic analyses, GSTs can conjugate glutathione to anticancer alkylating agents (2,3,9,49,59) [1606][1607][1608][1609][1610][1611][1612] 1991) and Ublacker et al. (Cancer Res 51: 1783-1788, 1991, based upon in vitro kinetic analyses, support our findings done in whole cells which show that the rat )I and a class GSTs catalyze the conjugation of GSH to monochlorobimane more efficiently than 71 class GSTs.

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Metabolism-related assays and their application to agrochemical research: reactivity of pesticides with glutathione and glutathione transferases†

Clarke¹,

Greenhow²,

Adams³

1998

Pestic. Sci.

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: An HPLC-based assay system has been developed to measure the reactivity of agrochemicals with glutathione (GSH) with and without catalysis by glutathione transferases (GSTs). Metabolism-related parameters based on second-order related rate constants from non-enzymatic GSH and enzymatic GSH ] GST assays have been derived for use in structureÈactivity and structureÈreactivity relationship studies of exploratory agrochemicals. The versatility and sensitivity of the assay system has been established using a diverse range of agrochemicals and model compounds, e.g. 4-nitrobenzyl chloride, 1-chloro-2,4-dinitrobenzene, atrazine, acetochlor, Ñuorodifen, Ñuazifop-butyl, tridiphane, Ñuazinam, chlorothalonil and diazinon. For the enzymatic GSH ] GST assay, second-order related rate constants, ratioed to the assay standard, 4-nitrobenzyl chloride to provide a parameter independent of assay conditions, spanned Ðve orders of magnitude, Ñuazinam being the most reactive and atrazine the least. Within chemical classes signiÐcant variations in reactivity were observed, alachlor being c.15-fold more reactive than pretilachlor. Applications of this assay system based on comparative measures of reactivity across and within chemical classes are discussed.1998 Society of Chemical Industry ( Pestic. Sci., 54, 385È393 (1998)

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Glutathione Transferases—Structure and Catalytic Activit

Cited by 1,736 publications

References 183 publications

Transport of the glutathione conjugate of ethacrynic acid by the human multidrug resistance protein MRP

Transport of the glutathione conjugate of ethacrynic acid by the human multidrug resistance protein MRP

Recombinant glutathione S‐transferase (GST) expressing cells purified by flow cytometry on the basis of a GST‐catalyzed intracellular conjugation of glutathione to monochlorobimane

Metabolism-related assays and their application to agrochemical research: reactivity of pesticides with glutathione and glutathione transferases†

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