Glutathione Transferases Catalyzing Leukotriene C Synthesis and Metabolism of Leukotrienes C4 and E4 in Vivo and in Vitro

Hammarström, Sven; Örning, Lars; Bernström, Kerstin; Gustafsson, Bengt E.; Norin, Elisabeth; Mannervik, Bengt; Jensson, Helgi; Ålin, Per

doi:10.1007/978-1-4684-4946-4_7

Cited by 5 publications

(9 citation statements)

References 15 publications

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“…5)). GGTs then cleave the -glutamyl moiety from LTC 4 to form the cysteinylglycine-adduct LTD 4 [91,105] (Fig. (5)), which is then converted to LTE 4 by dipeptidases [106,107].…”

Section: Metabolism Of Gsh-adductsmentioning

confidence: 99%

Endogenous Glutathione Adducts

Blair¹

2006

CDM

114

105

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This review provides an overview of the formation, pharmacology, and toxicology of endogenous glutathione (GSH)-adducts with particular emphasis on GSH-adducts that arise from lipid peroxidation. GSH is the major low-molecular-weight thiol in mammalian cells. It is involved in the formation of endogenous bioactive eicosanoids and is a source of reducing equivalents in a number of biosynthetic reactions. GSH has long been recognized to act as a co-factor in the reduction of reactive oxygen species and lipid hydroperoxides by glutathione peroxidases and glutathione-S-transferases (GSTs). It also plays an important role in the reduction of reactive intermediates derived from arylamines and in the conjugation of reactive intermediates to form S-substituted endogenous GSH-adducts through its nucleophilic cysteine sulfhydryl group. Although some reactive intermediates can form adducts directly, GST-mediated reactions generally predominate. This results in the formation of bioactive endogenous GSH-adducts derived from eicosanoids, isoprostanes, estrogens, catecholamines, and 4-hydroxy-2(E)-nonenal (HNE). Cellular oxidative stress causes increased lipid peroxidation with the concomitant formation of DNA- and protein-reactive bifunctional electrophiles. It has generally been considered that HNE is the most abundant bifunctional electrophile that is formed. Several years ago we discovered that 4-oxo-2(E)-nonenal (ONE) was also a major lipid hydroperoxide-derived bifunctional electrophile. From in vitro studies, we showed that ONE and HNE arose from the common intermediate, 4-hydroperoxy-2(E)-nonenal and also showed that ONE was formed in greater amounts than HNE. We have recently made the unexpected discovery that GSH addition to ONE leads to the formation of an unusual thiadiazabicyclo-ONE-GSH-adduct (TOG), which was characterized as (2S,7R) - 7 - [N - (carboxymethyl)carbamoyl] - 5 - oxo - 12 - pentyl - 9 - thia - 1,6 - diazabicyclo[8.2.1]trideca - 10(13), 11-diene-2-carboxylic acid. TOG is one of the most abundant GSH-adducts formed during peroxide/Fe(II)- or Fe(II)-mediated oxidative stress in EA.hy 926 endothelial cells. As TOG is formed from ONE, these experiments have confirmed that ONE is a major lipid hydroperoxide-derived bifunctional electrophile formed during intracellular oxidative stress. TOG represents the first member of a new class of endogenous GSH-adduct biomarkers that can be used to quantify intracellular oxidative stress. Two other members of the TOG family arise from GST-mediated GSH-adduct formation with dioxododecenoic acid and dioxooctenoic acid, bifunctional electrophiles derived from the carboxy terminus of lipid hydroperoxides. The formation of TOG and TOG-related endogenous GSH-adducts can result from free radical- as well as cyclooxygenase- and lipoxygenase-mediated pathways. Analysis of the GSH-adducts by stable isotope dilution mass spectrometry-based methodology will provide a quantitative measure of enzymatic and non-enzymatic cellular oxidative stress to complement isoprostane measurement...

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“…5)). GGTs then cleave the -glutamyl moiety from LTC 4 to form the cysteinylglycine-adduct LTD 4 [91,105] (Fig. (5)), which is then converted to LTE 4 by dipeptidases [106,107].…”

Section: Metabolism Of Gsh-adductsmentioning

confidence: 99%

Endogenous Glutathione Adducts

Blair¹

2006

CDM

114

105

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“…To prove the presumed mediator role of this substance in anaphylactic reactions, it is necessary to demonstrate its endogenous formation during anaphylaxis. Studies on LTC4 metabolism have revealed rapid catabolism by various transformations of the peptide substituent (15). Three metabolites have been demonstrated to be excreted as end-products: leukotriene E4 (LTE4) (16) in man and N-acetyl-LTE4 plus N-acetyl-11-trans-LTE4 (17) in the rat.…”

mentioning

confidence: 99%

“…The selectively labeled LTC4 [5,6,8,9,11,12,14,15-3H8]LTC4 (specific activity: 10 Ci/mmol; 0.37 TBq/mmol; 1 Ci = 37 GBq) was prepared as described (17,20). [14,15-3H(n)]LTD4 (leukotriene D4) (48 Ci/mmol) was from Amersham.…”

mentioning

confidence: 99%

Endogenous leukotriene D4 formation during anaphylactic shock in the guinea pig.

Keppler¹,

Örning²,

Bernström³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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Experiments on the metabolism and excretion of i.v. administered selectively labeled [3H8]1eukotriene C4 in bile duct-cannulated guinea pigs indicated predominantly biliary excretion of tritium. The major leukotriene metabolite in bile was identified as leukotriene D4. By monitoring leukotriene excretion radioimmunochromatographically, it was shown that guinea pigs suffering from anaphylactic shock produce leukotriene D4 endogenously. Immunological challenge of animals sensitized to ovalbumin was accompahied by an increase of biliary leukotriene D4 concentrations from 10 ± 1 to 86 ± 10 nM (mean ± SEM, n = 5, P < 0.001). When considering that bile flow was decreased to abobt half after challenge, the excretion rate of leukotriene D4 in bile increased from 0.88 ± 0.16 before to 3.18 ± 0.38 pmolmin-'-kg-' after challenge (mean ± SEM, n = 5, P < 0.002). It is concluded that systemic anaphylaxis in the guinea pig is associated with endogenous generation of leukotriene C4 (Up to 1 nmol/kg during a 30-min period after the challenge).Leukotriene C4 (LTC4) is a biologically active substance presumed to play major roles as a mediator of allergic and anaphylactic reactions (1, 2). It is formed by basophilic (3) and eosinophilic leukocytes (4), monocytes (5), macrophages (6), and mast cells (7). In cells having IgE receptors, bridging of these receptors by divalent anti-IgE receptor antibodies or by interaction between receptor-bound IgE and anti-IgE will induce LTC4 formation (5-7). Leukotriene formation has also been demonstrated in other in vitro models of immediate hypersensitivity (8-10). The biological actions of LTC4 comprise induction of airway obstruction, constriction of coronary arteries, hypotension, and plasma extravasation (11)(12)(13)(14). Leukotriene formation in vivo may mediate anaphylactic shock symptoms and cause the death of an animal. To prove the presumed mediator role of this substance in anaphylactic reactions, it is necessary to demonstrate its endogenous formation during anaphylaxis. Studies on LTC4 metabolism have revealed rapid catabolism by various transformations of the peptide substituent (15). Three metabolites have been demonstrated to be excreted as end-products: leukotriene E4 (LTE4) (16) in man and N-acetyl-LTE4 plus N-acetyl-11-trans-LTE4 (17) in the rat. By monitoring biliary N-acetyl-LTE4 levels, endogenous leukotriene formation in the rat was demonstrated in vivo after tissue trauma and endotoxin shock (18,19). We now wish to report evidence for endogenous LTC4 production during anaphylactic shock in guinea pigs.

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“…This is in contrast to the hepatocytes that generated additionally more polar metabolites also described as intracellular products [XI. Moreover, N-acetyl-LTE,, which was recently identified as a product of LTC, metabolism in the rat [22,23], was not detectable in the suspension of AS-30D rat hepatoma cells, whereas a metabolitc comigrating on HPLC with synthetic N-acetyl-LTE, was observed in the medium of rat hepatocytes. This suggests that N-acetylation of LTE, only occurs in cells capable of taking up cysteinyl leukotrienes.…”

Section: Discussionmentioning

confidence: 82%

Leukotriene C₄ metabolism by hepatoma cells deficient in the uptake of cysteinyl leukotrienes

Weckbecker

Keppler

1986

European Journal of Biochemistry

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Uptake and metabolism of the cysteinyl leukotrienes C4 and E4 (LTC, and LTE,) were studied in AS-30D hepatoma cell suspensions and compared with rat hepatocytes. The hepatoma cells were deficient in the uptake of ['HILTC, and ['HILTE, but We conclude that ectoenzymes of AS-30D hepatoma cells catalyze the conversion of LTC, to LTE, via LTD4. As compared to hepatocytes, these neoplastic cells have lost the uptake system for cysteinyl leukotrienes and may serve in studies on leukotriene metabolism by cell-surface enzymes.The leukotriene constituents of slow-reacting substance of anaphylaxis LTC,, LTD, and LTE, are rapidly eliminated from blood plasma [I -31. A major portion of intravenously injected cysteinyl leukotrienes is taken up by the liver and excreted into bile in rats [4, 51, mice [6] and guinea-pigs [7]. Hepatocytes as well as kidney cells are characterized by an efficient uptake system for cysteinyl leukotrienes [8, 93. In addition to peptide cleavage of LTC, yielding LTD, and LTE,, the formation of polar metabolites of cysteinyl leukotrienes has been demonstrated [6, 81. Studies on the rnetabo h m of cysteinyl leukotrienes require the discrimination between metabolic reactions catalyzed by ectoenzymes located on the cell surface and intracellular reactions. A discrimination between these two metabolic compartments is possible by the use of cells deficient in the uptake system for cysteinyl leukotrienes. In this report we describe a hepatoma cell line, which is capable of metabolizing extracellular LTC, to LTE4 via LTD4 but shows, in contrast to hepatocytes, no uptake of cysteinyl leukotrienes.

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Glutathione Transferases Catalyzing Leukotriene C Synthesis and Metabolism of Leukotrienes C4 and E4 in Vivo and in Vitro

Cited by 5 publications

References 15 publications

Endogenous Glutathione Adducts

Endogenous Glutathione Adducts

Endogenous leukotriene D4 formation during anaphylactic shock in the guinea pig.

Leukotriene C₄ metabolism by hepatoma cells deficient in the uptake of cysteinyl leukotrienes

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Glutathione Transferases Catalyzing Leukotriene C Synthesis and Metabolism of Leukotrienes C4 and E4 in Vivo and in Vitro

Cited by 5 publications

References 15 publications

Endogenous Glutathione Adducts

Endogenous Glutathione Adducts

Endogenous leukotriene D4 formation during anaphylactic shock in the guinea pig.

Leukotriene C4 metabolism by hepatoma cells deficient in the uptake of cysteinyl leukotrienes

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Leukotriene C₄ metabolism by hepatoma cells deficient in the uptake of cysteinyl leukotrienes