Hepatobiliary elimination of the peroxisome proliferator nafenopin by conjugation and subsequent atp-dependent transport across the canalicular membrane

Gabriele Jedlitschky*, Inka Leier, Matthias Böhme, Ulrike Buchholz, Jacob Bar-Tana, Dietrich Keppler

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Amphiphilic carboxylates acting as peroxisome proliferators and hypolipidemic drugs induce enzymes of peroxisomal lipid β-oxidation, certain drug-metabolizing enzymes in the liver, and a number of additional proteins. The peroxisome proliferators represent a well-established class of non-genotoxic hepatocarcinogens. In this study we characterized the hepatic elimination of the peroxisome proliferator nafenopin. In the rat in vivo, 1 hr after intravenous administration of [3H]nafenopin, approx. 40% of injected radioactivity was recovered in bile. HPLC analysis of bile samples revealed that only about 10% of the radioactivity recovered in bile was associated with non-metabolized nafenopin and approx. 90% with more polar metabolites. One of the main metabolites formed in the liver and excreted into bile was identified as nafenopin glucuronide by β-glucuronidase-catalysed reconversion to nafenopin. In mutant rats deficient in the canalicular transport of leukotriene C4 and related amphiphilic anion conjugates, recovery of [3H]nafenopin-derived radioactivity in bile was reduced to 4% of the injected dose. Although nafenopin glucuronide could not be detected in bile, it was a major metabolite in the liver from these mutant rats. Using membrane vesicles enriched in bile canalicular membranes from normal rats, transport of nafenopin glucuronide was shown to be a primary-active ATP-dependent process which was inhibited by leukotriene C4 and S-dinitrophenyl glutathione with IC50 values of 0.2 and 12 μM, respectively. ATP-dependent transport was not detectable for non-conjugated nafenopin. In canalicular membrane vesicles prepared from the mutant rats, the rate of ATP-dependent transport of nafenopin glucuronide was less than 10% of the transport observed in vesicles from normal rats. These data indicate that conjugation and subsequent transport by the ATP-dependent export carrier for leukotriene C4 and related conjugates is a major pathway for the elimination of nafenopin and structurally-related peroxisome proliferators.

Original languageEnglish
Pages (from-to)1113-1120
Number of pages8
JournalBiochemical Pharmacology
Volume48
Issue number6
DOIs
StatePublished - 15 Sep 1994

Keywords

  • ATP-dependent transport
  • bile canalicular membrane
  • leukotriene C
  • nafenopin
  • nafenopin glucuronide
  • peroxisome proliferator

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