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

Biochem Pharmacol. 1994 Sep 15;48(6):1113-20. doi: 10.1016/0006-2952(94)90147-3.

Abstract

Amphiphilic carboxylates acting as peroxisome proliferators and hypolipidemic drugs induce enzymes of peroxisomal lipid beta-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 beta-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 microM, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Bile / metabolism
  • Bile Canaliculi / metabolism*
  • Bile Canaliculi / ultrastructure
  • Biological Transport
  • Glucuronates / metabolism
  • Liver / metabolism*
  • Male
  • Mutation
  • Nafenopin / metabolism*
  • Rats
  • Rats, Wistar
  • Tritium

Substances

  • Glucuronates
  • Nafenopin
  • Tritium
  • Adenosine Triphosphate