Piperine activates human pregnane X receptor to induce the expression of cytochrome P450 3A4 and multidrug resistance protein 1

Toxicol Appl Pharmacol. 2013 Oct 1;272(1):96-107. doi: 10.1016/j.taap.2013.05.014. Epub 2013 May 22.


Activation of the pregnane X receptor (PXR) and subsequently its target genes, including those encoding drug transporters and metabolizing enzymes, while playing substantial roles in xenobiotic detoxification, might cause undesired drug-drug interactions. Recently, an increased awareness has been given to dietary components for potential induction of diet-drug interactions through activation of PXR. Here, we studied, whether piperine (PIP), a major component extracted from the widely-used daily spice black pepper, could induce PXR-mediated expression of cytochrome P450 3A4 (CYP3A4) and multidrug resistance protein 1 (MDR1). Our results showed that PIP activated human PXR (hPXR)-mediated CYP3A4 and MDR1 expression in human hepatocytes, intestine cells, and a mouse model; PIP activated hPXR by recruiting its coactivator SRC-1 in both cellular and cell-free systems; PIP bound to the hPXR ligand binding domain in a competitive ligand binding assay in vitro. The dichotomous effects of PIP on induction of CYP3A4 and MDR1 expression observed here and inhibition of their activity reported elsewhere challenges the potential use of PIP as a bioavailability enhancer and suggests that caution should be taken in PIP consumption during drug treatment in patients, particularly those who favor daily pepper spice or rely on certain pepper remedies.

Keywords: CYP; Cytochrome P450 3A4; KET; MDR1; Multidrug resistance protein 1; PCN; PIP; PXR; Piperine; Pregnane X receptor; RIF; SRC-1; T0901317; TO; cytochrome P450; drug–drug interaction; ketoconazole; multidrug resistance protein 1; piperine; pregnane X receptor; pregnenolone-16α-carbonitrile; rifampicin; steroid receptor coactivator-1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis*
  • Alkaloids / pharmacology*
  • Animals
  • Benzodioxoles / pharmacology*
  • Binding, Competitive / drug effects
  • Cell Line
  • Chimera / genetics
  • Cytochrome P-450 CYP3A / biosynthesis*
  • Hemodynamics / drug effects
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Nuclear Receptor Coactivator 2 / pharmacology
  • Piperidines / pharmacology*
  • Plasmids / genetics
  • Polyunsaturated Alkamides / pharmacology*
  • Pregnane X Receptor
  • RNA / biosynthesis
  • RNA / isolation & purification
  • RNA, Small Interfering / pharmacology
  • Real-Time Polymerase Chain Reaction
  • Receptors, Steroid / agonists*
  • Transcriptional Activation / drug effects


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Alkaloids
  • Benzodioxoles
  • Nuclear Receptor Coactivator 2
  • Piperidines
  • Polyunsaturated Alkamides
  • Pregnane X Receptor
  • RNA, Small Interfering
  • Receptors, Steroid
  • RNA
  • Cytochrome P-450 CYP3A
  • piperine