title: Uptake, production and metabolism of cysteinyl leukotrienes in the isolated perfused rat liver. Inhibition of leukotriene uptake by cyclosporine.
abstract: 1. The isolated perfused rat liver efficiently takes up cysteinyl leukotrienes (LTs) C4, D4, E4 and N-acetyl-LTE4 from circulation. More than 70% of these cysteinyl LTs are excreted from liver into bile within 1 h of onset of a 5 min infusion, while about 5% remain in the liver. About 20% of infused N-acetyl-LTE4 escapes hepatic first-pass extraction under our conditions. 2. Metabolites of LTC4 appearing in bile within 20 min of the onset of infusion include mainly LTD4 and N-acetyl-LTE4, but also omega-hydroxy-N-acetyl-LTE4 and omega-carboxy-N-acetyl-LTE4. Metabolites generated from omega-carboxy-N-acetyl-LTE4 by beta-oxidation from the omega-end represent the major biliary LTs secreted at later times. 3. Stimulation of the isolated perfused liver by the combined infusion of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and the Ca2+ ionophore A23187 results in a transient increase of endogenous cysteinyl LT production, which is independent of extrahepatic cells. 4. The immunosuppressive drug cyclosporine causes a dose-dependent inhibition of hepatobiliary cysteinyl LT excretion, probably by interference with the sinusoidal uptake system for cysteinyl LTs.
authors.affiliation: Deutsches Krebsforschungszentrum, Heidelberg, Federal Republic of Germany.
authors.forename: W
authors.initials: W
authors.lastname: Hagmann
authors.forename: S
authors.initials: S
authors.lastname: Parthé
authors.forename: I
authors.initials: I
authors.lastname: Kaiser
mesh_terms: D000818:Animals; D003524:Cyclosporins / Q000494:pharmacology*; D017999:Leukotriene E4 / Q000031:analogs & derivatives; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D003524:Cyclosporins; D013189:SRS-A; D017999:Leukotriene E4; C047630:N-acetylleukotriene E4