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Regulation of drug transporter expression by oncostatin M in human hepatocytes

Marc Le Vee1, Elodie Jouan, Bruno Stieger

  • 1EA 4427 SeRAIC, Institut de Recherches Santé, Environnement et Travail, Université de Rennes 1, Département HITC, Hôpital Pontchaillou, CHU, 2 Avenue du Pr L. Bernard, 35043 Rennes, France.

Biochemical Pharmacology
|May 17, 2011
PubMed

Insights

Oncostatin M (OSM) reduces key drug transporters in human liver cells, impacting drug metabolism and clearance. This finding is linked to inflammatory diseases and suggests potential pharmacokinetic changes in patients.

Area of Science:

  • Hepatology and Pharmacology
  • Molecular Biology and Drug Transport

Background:

  • Oncostatin M (OSM), an IL-6 family cytokine, is known to decrease drug-metabolizing cytochrome P-450 expression in human hepatocytes.
  • Hepatic drug transporters, both sinusoidal influx and canalicular efflux, are critical for drug hepatic clearance.

Purpose of the Study:

  • To investigate the effect of OSM on the expression and function of sinusoidal and canalicular drug transporters in primary human hepatocytes.
  • To understand the clinical implications of OSM-mediated transporter alterations in liver diseases.

Main Methods:

  • Primary human hepatocytes were exposed to OSM.
  • mRNA and protein levels of various drug transporters (SLC and ABC families) were quantified.
  • Hepatocyte transport activities were measured, and OSM receptor subunit expression was modulated using siRNA.

Main Results:

  • OSM significantly down-regulated mRNA expression of major influx transporters (NTCP, OATP1B1, OATP1B3, OATP2B1, OCT1, OAT2) and efflux transporters (MRP2/ABCC2, BCRP/ABCG2).
  • OSM reduced protein levels of NTCP, OATP1B1, OATP2B1, and ABCG2, along with NTCP and OATP transport activities.
  • OSM's effects were dose-dependent, correlated with IL-6, and partially mediated by the type II OSM receptor.

Conclusions:

  • OSM impairs the expression and function of critical drug influx and efflux transporters in human hepatocytes.
  • This OSM-induced down-regulation may contribute to altered pharmacokinetics in patients with conditions involving elevated OSM levels.

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