Leukotriene C<sub>4</sub> metabolism by hepatoma cells deficient in the uptake of cysteinyl leukotrienes

Weckbecker, Gisbert; Keppler, Dietrich

doi:10.1111/j.1432-1033.1986.tb09435.x

Cited by 27 publications

(7 citation statements)

References 21 publications

(4 reference statements)

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“…Unlabelled LTC4, LTD4, LTE4 and N-acetyl-LTE4 were purchased from Paesel (Frankfurt, FRG), [5,6,8,9,11,12,14, 1 5(n)-3H]LTC4 (8.14 TBq . mmol-'), [5,6,8,9,11,12,14,15(n)-3H]LTD4 (7.1 TBq . mmol-') and [5,6,8,9,11,12,14,15(n)-3H]LTE4 (7.1 TBq .…”

Section: Chemirahmentioning

confidence: 99%

Characteristics of sinusoidal uptake and biliary excretion of cysteinyl leukotrienes in perfused rat liver

Wettstein

Gerok

Häussinger

1990

European Journal of Biochemistry

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In single-pass perfused rat liver, the sinusoidal uptake ofinfused 3H-labelled leukotriene (LT) C4 (10 nmol . 1-') was inhibited by sulfobromophthalein. Inhibition was half-maximal at sulfobromophthalein concentrations of approximately 1.2 pmol . 1-' in the influent perfusate and leukotriene uptake was inhibited by maximally 34%.Sulfobromophthalein (20 pmol . 1-I) also decreased the uptake of infused [3H]LTE4 (10 nmol . I-') by 31%.Indocyanine green (10 pmol . 1-') inhibited the sinusoidal [3H]LTC4 uptake by 19%.Replacement of sodium in the perfusion medium by choline decreased the uptake of infused [3H]LTC4(10 nmol . 1-') by 56%, but was without effect on the uptake of sulfobromophthalein.The canalicular excretion of LTC4, LTD4 and N-acetyl-LTE, was inhibited by sulfobromophthalein. In contrast, the proportion of polar w-oxidation metabolites recovered in bile following the infusion of [3H]LTC4 was increased. Taurocholate, which had no effect on the sinusoidal leukotriene uptake, increased bile flow and also the biliary elimination of the radioactivity taken up. With increasing taurocholate additions, the amount of LTD, recovered in bile increased at the expense of LTC4.Following the infusion of [3H]LTD4 (10 nmol . 1-I), a major biliary metabolite was LTC4 indicating a reconversion of LTD, to LTC,. In the presence of taurocholate (40 pmol . 1-I), however, this reconversion was completely inhibited.The findings suggest the involvement of different transport systems in the sinusoidal uptake of cysteinyl leukotrienes. LTC4 uptake is not affected by bile acids and has a sodium-dependent and a sodium-independent component, the latter probably being shared with organic dyes. Sulfobromophthalein also interferes with the canalicular transport of LTC4, LTD4 and N-acetyl-LTE4, but not with the excretion of w-oxidized cysteinyl leukotrienes. The data may be relevant for the understanding of hepatic leukotriene processing in conditions like hyperbilirubinemia or cholestasis.The cysteinyl leukotrienes (LT) LTC4, LTD4 and LTE4, potent lipid mediators of inflammation, are effectively eliminated from circulating blood [l]. In a variety of species the liver is the major site of leukotriene uptake [2-51, whereas in ximates both biliary and urinary excretion contribute to the :limination of cysteinyl leukotrienes [6, 71. Hepatic processing of leukotrienes includes extracellular degradation of LTC4 to LTD4 and LTE4 catalyzed by the ectoenzymes y-glutamyltransferase and y-glutamyldipeptidase [S], uptake into the hepatocytes, intracellular metabolism and biliary excretion. In rat livers, LTE4 is intracellularly Nacetylated [9, lo], followed by w-oxidation and subsequent chain shortening by /?-oxidation from the w-carboxyl end [l 1 -131. The biliary compartment most likely also contributes to leukotriene metabolism by interconverting biliary LTC4 and LTD4 due to the high activity of y-glutamyltransferase in the canalicular and bile duct membranes ~4 1 .

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Section: Chemirahmentioning

confidence: 99%

Characteristics of sinusoidal uptake and biliary excretion of cysteinyl leukotrienes in perfused rat liver

Wettstein

Gerok

Häussinger

1990

European Journal of Biochemistry

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“…4). In the sinusoidal space, LTC, is partly converted to LTD, and LTE, by the ectoenzymes y-glutamyl-transferase and dipeptidase (19). LTC,, LTD, and LTE, are taken up very effectively by the hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia and CCI4-induced liver injury, but not acidosis, impair metabolism of cysteinyl leukotrienes in perfused rat liver

Wettstein¹,

Gerok²,

Häussinger³

1990

Hepatology

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Uptake, metabolism and biliary elimination of infused cysteinyl leukotrienes were investigated in single-pass perfused rat liver. Hypoxia did not impair uptake of infused [3H]leukotriene C4, but inhibited biliary excretion of radioactivity by about 50% compared with normoxic control experiments. In addition, the leukotriene metabolite pattern in bile was profoundly altered and was characterized in hypoxia by a 75% to 80% decrease of both leukotriene C4 and polar metabolites, representing omega-oxidation products, whereas the appearance of leukotriene D4 in bile was not affected. Reoxygenation was followed by a marked increase of biliary excretion of polar metabolites, indicating that leukotrienes taken up and stored in the liver cells during the hypoxic period now underwent omega-oxidation with subsequent elimination of the omega-oxidized products. Hypoxia also inhibited the biliary excretion of radioactivity after [3H]leukotriene E4 addition because of an almost complete absence of omega-oxidation products in bile, whereas N-acetyl-leukotriene E4 excretion was not affected. Induction of liver injury by carbon tetrachloride treatment decreased single-pass uptake of [3H]leukotriene C4 by 30%, and only 36% of the radioactivity taken up by the liver was eliminated into bile within 1 hr, compared with 78% in normal livers. The pattern of biliary leukotriene metabolites, however, was not significantly different. Lowering the pH in the perfusion medium from 7.4 to 7.1 had no effect on uptake, metabolism or biliary elimination of infused [3H]leukotriene C4. The data show that hypoxia and experimental liver injury, but not acidosis, impair hepatic processing of cysteinyl leukotrienes. Thus, in leukotriene-induced shock syndromes, leukotriene elimination and inactivation may be impaired giving rise to a "vicious circle."

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“…Cysteinyl leukotrienes were separated using a reversed-phase high-pressure liquid chromatography system with a Beckman Ultrasphere-ODS column (Beckman, Fullerton, CA, 4.6 x 250 mm, 5-pm particles). The mobile phase consisted of a linear gradient from 85% solvent A (methanol/ watedacetic acid 5/95/0.1% by volume, pH adjusted to 5.0 with ammonium chloride) and 15% solvent B (20 volumes of water containing 0.1% acetic acid, pH adjusted to 5.0, then addition of 80 volumes methanol) to 70% solvent A and 30% solvent B within 30 minutes. The flow rate was 1 mumin.…”

Section: Methodsmentioning

confidence: 99%

Metabolism of cysteinyl leukotrienes in the perfused rat liver: The influence of endotoxin pretreatment and the cellular hydration state

1995

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The influence of endotoxin on the hepatic metabolism and elimination of 3H-leukotriene C4 (LTC4) and 3H-leukotriene E4 was studied in the single-pass perfused rat liver. Endotoxin (4 mg/kg body mass) was injected intraperitoneally 8 to 10 hours before livers were isolated for perfusion. Tritiated leukotriene C4 and leukotriene E4 (10 nmol/L) were infused for 5 minutes, and metabolites in bile were determined by high-pressure liquid chromatography. In livers without endotoxin pretreatment, single-pass uptake of LTC4 was 77.3% +/- 3.2%, and 73.8% +/- 1.8% of the radioactivity taken up was excreted into the bile within 80 minutes. In endotoxin-pretreated livers, LTC4 uptake was 62.8% +/- 3.5% and only 31.2% +/- 1.5% of the radioactivity taken up was eliminated into the bile within 80 minutes. Bile flow was reduced to 0.20 +/- 0.07 microL/min, compared with 1.18 +/- 0.18 microL/g/min in untreated livers. Biliary excretion of infused 3H-LTE4 was also reduced in endotoxin-pretreated livers (31.5% +/- 6.1% compared with 61.4% +/- 3.3% without endotoxin pretreatment), whereas uptake was not significantly different. The effect of cellular hydration state on leukotriene processing was also investigated. Anisoosmotic cell volume changes did not influence uptake and biliary excretion of 3H-LTC4 and its metabolism in control livers. In endotoxin-pretreated livers, however, cell swelling induced by hypotonic perfusion media (225 mOsm/L) or by 3 mmol/L glutamine increased biliary elimination of the radioactivity taken up by 68% and 54%, respectively. Bile flow was also stimulated (0.31 +/- 0.09 microL/g/min and 0.46 +/- 0.01 microL/g/min, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

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

Cited by 27 publications

References 21 publications

Characteristics of sinusoidal uptake and biliary excretion of cysteinyl leukotrienes in perfused rat liver

Characteristics of sinusoidal uptake and biliary excretion of cysteinyl leukotrienes in perfused rat liver

Hypoxia and CCI4-induced liver injury, but not acidosis, impair metabolism of cysteinyl leukotrienes in perfused rat liver

Metabolism of cysteinyl leukotrienes in the perfused rat liver: The influence of endotoxin pretreatment and the cellular hydration state

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

Cited by 27 publications

References 21 publications

Characteristics of sinusoidal uptake and biliary excretion of cysteinyl leukotrienes in perfused rat liver

Characteristics of sinusoidal uptake and biliary excretion of cysteinyl leukotrienes in perfused rat liver

Hypoxia and CCI4-induced liver injury, but not acidosis, impair metabolism of cysteinyl leukotrienes in perfused rat liver

Metabolism of cysteinyl leukotrienes in the perfused rat liver: The influence of endotoxin pretreatment and the cellular hydration state

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