Pharmaceutical Research

, Volume 15, Issue 5, pp 706–711

Decreased Expression and Activity of P-GIycoprotein in Rat Liver During Acute Inflammation

  • Micheline Piquette-Miller
  • Anne Pak
  • Hani Kim
  • Reza Anari
  • Afshin Shahzamani
Article

DOI: 10.1023/A:1011962818051

Cite this article as:
Piquette-Miller, M., Pak, A., Kim, H. et al. Pharm Res (1998) 15: 706. doi:10.1023/A:1011962818051

Abstract

Purpose. Drug disposition is often altered in inflammatory disease. Although the influence of inflammation on hepatic drug metabolism and protein binding has been well studied, its impact on drug transport has largely been overlooked. The multidrug resistance (MDR) gene product, P-glycoprotein (P-gp) is involved in the active secretion of a large variety of drugs. Our goal was to ascertain the influence of acute inflammation (AI) on the expression and functional activity of P-gp.

Methods. AI was induced in rats through turpentine or lipopolysaccharide (LPS) administration. Expression of P-gp in liver was detected at the level of protein on Western blots using the monoclonal antibody C-219 and at the level of mRNA using an RNase protection assay. P-gp mediated transport activity was assessed by measuring the verapamil-inhibitable efflux of rhodamine 123 (R123) in freshly isolated hepatocytes.

Results. Turpentine-induced AI significantly decreased the hepatic protein expression of P-gp isoforms by 50−70% and caused a significant 45−65% reduction in the P-gp mediated efflux of R123. Diminished mRNA levels of all three MDR isoforms were seen. LPS-induced AI similarly resulted in significantly reduced levels and activity of P-gp in liver. Although differences in the constitutive levels of P-gp were seen between male and female rats, the influence of AI on P-gp expression and activity was not gender specific.

Conclusions. Experimentally-induced inflammation decreases the in vivo expression and activity of P-gp in liver. This is the first evidence that expression of P-gp is modulated in response to experimentally-induced inflammation.

multidrug resistance P-glycoprotein inflammation acute phase response gene regulation drug disposition 

Copyright information

© Plenum Publishing Corporation 1998

Authors and Affiliations

  • Micheline Piquette-Miller
    • 1
  • Anne Pak
  • Hani Kim
    • 1
  • Reza Anari
    • 1
  • Afshin Shahzamani
    • 1
  1. 1.Faculty of PharmacyUniversity of TorontoTorontoCanada