Metabolic inactivation of leukotrienes.
The metabolic inactivation of the cysteinyl leukotrienes LTC4 and LTD4 and of the chemotactic LTB4 was studied in the rat in vivo and in hepatocyte suspensions, respectively. 1. Deactivation of LTC4 via LTD4 to LTE4 was a most active process in the blood circulation, catalyzed mainly by ectoenzymes located on the internal wall of blood vessels. Uptake of cysteinyl leukotrienes by hepatocytes and kidney cells contributed to the rapid elimination of these potent mediators whenever they were released into the blood circulation. The initial half-life of LTC4 in vivo was 12 seconds. 2. omega-Oxidation leads to the formation of omega-hydroxylated and omega-carboxylated cysteinyl leukotrienes which were detected in bile and urine. Biliary metabolites included those formed by stepwise beta-oxidative degradation of omega-carboxy-N-acetyl-LTE4, yielding the dinor, tetranor, and hexanor derivative. 3. The peroxisome proliferator clofibrate strongly increased the degradation of LTE4 by omega-oxidation and subsequent beta-oxidation in vivo. The generation of new polar metabolites was detected by HPLC methods and by the use of 3H8-labeled cysteinyl leukotrienes in comparison with the 3H2-labeled precursor. 4. The metabolic degradation and inactivation of cysteinyl leukotrienes in vivo and of LTB4 in isolated hepatocytes was potently inhibited by ethanol. The site of inhibition was the oxidation of omega-hydroxy-N-acetyl-LTE4 and of omega-hydroxy-LTB4 to the respective omega-carboxylated metabolite. This inhibition led to an accumulation of the biologically active LTB4 and of N-acetyl-LTE4. The interference of leukotriene inactivation in the liver may provide a novel explanation for the ethanol-induced inflammatory reaction in acute alcoholic liver disease.
Keppler
D
D
Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Federal Republic of Germany.
Huber
M
M
Baumert
T
T
Guhlmann
A
A
D000818:Animals; D001646:Bile / Q000378:metabolism; D002478:Cells, Cultured; D002994:Clofibrate / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D005246:Feedback; D007700:Kinetics; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000302:isolation & purification / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D051381:Rats; D013189:SRS-A / Q000378:metabolism*
D020024:Leukotriene Antagonists; D015289:Leukotrienes; D013189:SRS-A; D000431:Ethanol; D002994:Clofibrate