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

Abstract

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 xenobiotics 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 cautions should be taken for PIP consumption during drug treatment in patients, particularly those who favor daily pepper spice or rely on certain pepper remedies.

Nigramide C Is a Natural Agonist of Human Pregnane X Receptor

“…Although these compounds function as insecticides in the original plant (Siddiqui et al, 2005), in mammalian systems they function as inhibitors of various xenobiotic metabolizing enzymes such as CYP3A4 and transporters represented by ATP-binding cassette subfamily B member 1 (also known as P-glycoprotein or MDR1) upon acute exposure. Although upregulation of PXR target genes, such as CYP3A4 and MDR1, was observed after long-term exposure to 11 (Wang et al, 2013), we did not observe a significant activation of hPXR by the monomer-type compounds 10 and 11 ( Fig. 2A).…”

Effect of GBOT on blood lipid and blood glucose metabolism in rats with atherosclerosis

“…The level of very-low-density lipoprotein cholesterol increases in the blood (Banji et al, 2013). The TRL residue is an important part of small and dense low-density lipoprotein, and the latter has a closer relationship with atherosclerosis than low-density lipoprotein cholesterol level (Wang et al, 2013b).…”

CINPA1 Is an Inhibitor of Constitutive Androstane Receptor That Does Not Activate Pregnane X Receptor

“…5A). We also examined various cell lines and identified LS174T as moderately expressing endogenous CAR and its downstream targets; LS174T has previously been reported to express endogenous PXR with inducible activity (Wang et al, 2013). In HepG2-hCAR1, where CAR but not PXR is overexpressed and known to be constitutively active, CINPA1 substantially and significantly attenuated the levels of both endogenous CYP2B6 and CYP3A4 genes although PK11195 attenuated the level of CYP2B6 without significantly affecting that of CYP3A4 (Fig.…”

“…Plasmids used for mammalian two-hybrid assays, pG5-Luc (a GAL4-luciferase reporter construct) and pACT, were obtained from Promega (CheckMate). The pBIND-SRC-1 (621-765) plasmid was previously described (Wang et al, 2013). The pBINDmNCoR (1958-2401) and pBIND-SMRTa (2004-2517 plasmids were constructed as previously described (Wang et al, 2013).…”

“…The pBIND-SRC-1 (621-765) plasmid was previously described (Wang et al, 2013). The pBINDmNCoR (1958-2401) and pBIND-SMRTa (2004-2517 plasmids were constructed as previously described (Wang et al, 2013). The pACThCAR1 plasmid was prepared by polymerase chain reaction (PCR) amplification of hCAR1 by using oligonucleotides 59-GTA CCG AGC TCG GAT CCA ACT AGT AA-39 and 59-CAG GAT CCG CGG CCG CTC AGC TGC AGA T-39, digested using BamHI (Promega) and NotI (Promega) and ligating the resulting fragment into BamHI-and NotIcleaved pACT vector plasmid at a 1:7 molar ratio.…”