Regulation of transporters by nuclear hormone receptors: implications during inflammation

Mol Pharm. 2008 Jan-Feb;5(1):67-76. doi: 10.1021/mp700102q. Epub 2007 Dec 12.

Abstract

Membrane transporters play a critical role in the absorption, distribution, and elimination of both endogenous substrates and xenobiotics. Defects in transporter function can lead to altered drug disposition including toxicity or loss of efficacy. Inflammation is one condition during which variable drug response has been demonstrated, and this can be attributed, at least in part, to changes in the expression of transporter genes. Thus, knowledge of the mechanisms behind transporter regulation can significantly contribute to our ability to predict variations in drug disposition among individuals and during inflammatory disease. The discovery of several xenobiotic-activated nuclear hormone receptors during the past decade including the pregnane X receptor, constitutive androstane receptor, and farnesoid X receptor has contributed greatly toward this endeavor. These receptors regulate the expression of transporters such as P-glycoprotein, MRP2, MRP3, BCRP, and OATP2 (Oatp1a1/OATP1B1), all of which undergo altered expression during an inflammatory response. Nuclear receptors may therefore play an important role in mediating this effect. This review presents what is currently known about the role of nuclear receptors in transporter regulation during inflammation. The use of this knowledge toward understanding interindividual variation in drug response and drug interactions during inflammation as well toward the development of therapeutics to treat transporter-related diseases will also be discussed.

Publication types

  • Review

MeSH terms

  • Animals
  • Biological Transport
  • Gene Expression Regulation*
  • Humans
  • Inflammation
  • Membrane Transport Proteins / metabolism*
  • Receptors, Cytoplasmic and Nuclear / metabolism*

Substances

  • Membrane Transport Proteins
  • Receptors, Cytoplasmic and Nuclear