Hereditary defect of hepatobiliary cysteinyl leukotriene elimination in mutant rats with defective hepatic anion excretion

Authors

  • Michael Huber,

    1. Biochemisches Institut, Universitöt Freiburg, Freiburg i. Br. Federal Republic of Germany
    2. Division of Gastrointestinal and Liver Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    Search for more papers by this author
  • Albrecht Guhlmann,

    1. Biochemisches Institut, Universitöt Freiburg, Freiburg i. Br. Federal Republic of Germany
    2. Division of Gastrointestinal and Liver Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    Search for more papers by this author
  • Peter L. M. Jansen,

    1. Biochemisches Institut, Universitöt Freiburg, Freiburg i. Br. Federal Republic of Germany
    2. Division of Gastrointestinal and Liver Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    Search for more papers by this author
  • Dietrich Keppler

    Corresponding author
    1. Biochemisches Institut, Universitöt Freiburg, Freiburg i. Br. Federal Republic of Germany
    2. Division of Gastrointestinal and Liver Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    • Biochemisches Institut der Universität Freiburg, Hermann-Herder-Str. 7, D-7800 Freiburg, Federal Republic of Germany
    Search for more papers by this author

Abstract

Hepatobiliary and renal elimination of cysteinyl leu-kotrienes were investigated in a mutant rat strain with a hereditary defect in the hepatobiliary excretion of conjugated bilirubin, dibromosulfophthalein and oua-bain. After intravenous injection of [3H]leukotriene C4, the initial half-life of radioactivity circulating in blood was 79 ± 15 sec (S.D.) in transport mutant rats as compared to 31 ± 6 sec (S.D.) in normal Wistar rats. The intrahepatic leukotriene radioactivity was increased 5-fold after 1 hr in mutant rats, while the biliary elimination of [3H]Ieukotrienes was reduced to 1.8% of control. In normal rats, 77 ± 7% (S.D.) of the administered leukotriene radioactivity were recovered in bile within 1 hr. The total recovery of radioactivity from bile, urine, liver, intestine, stomach, kidneys, muscular system and blood 1 hr after intravenous [3H]leukotriene C4 was 89 ± 6% (S.D.) in normal rats and 46 ± 4% (S.D.) in transport mutants. Enterohepatic circulation was studied after intraduodenal administration of N-acetyl-[3H]leukotriene E4, a major cysteinyl leukotriene metabolite in rat bile. In transport mutants, hepatobiliary elimination of the intestinally absorbed [3H]leukotriene was reduced to 5%, whereas urinary excretion was not significantly affected. [3H]Leukotriene metabolites in bile, liver and urine were separated by reversed-phase high-performance liquid chromatography. The proportion of N-acetyl-[3H]leukotriene E4 relative to polar leukotriene metabolites was higher in the bile of transport mutants as compared to control Wistar rats when analyzed within 30 to 60 min after intravenous injection of [3H]leukotriene C4. Our results indicate that the cysteinyl leukotrienes are physiological substrates of the can-alicular transport system for organic anions such as dibromosulfophthalein. The transport mutant rats serve to characterize the hepatobiliary excretion system for cysteinyl leukotrienes.

Ancillary