Vitamin D Receptor-Mediated Upregulation of CYP3A4 and MDR1 by Quercetin in Caco-2 cells

Abstract

To examine whether quercetin interacts with vitamin D receptor, we investigated the effects of quercetin on vitamin D receptor activity in human intestinal Caco-2 cells. The effects of quercetin on the expression of the vitamin D receptor target genes, vitamin D3 24-hydroxylase, cytochrome P450 3A4, multidrug resistance protein 1, and transient receptor potential vanilloid type 6 were measured using quantitative polymerase chain reaction. The vitamin D receptor siRNA was used to assess the involvement of the vitamin D receptor. Vitamin D receptor activation using a vitamin D responsive element-mediated cytochrome P450 3A4 reporter gene assay was investigated in Caco-2 cells transfected with human vitamin D receptor. We also studied the magnitude of the vitamin D receptor activation and/or synergism between 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] and quercetin-like flavonoids. Slight but significant increases in the mRNA expression of cytochrome P450 3A4, vitamin D3 24-hydroxylase, multidrug resistance protein 1, and transient receptor potential vanilloid type 6 were observed after 3 days of continual quercetin treatment. The silencing effect of vitamin D receptor by vitamin D receptor siRNA in Caco-2 cells significantly attenuated the induction of the vitamin D receptor target genes. Moreover, quercetin significantly enhanced cytochrome P450 3A4 reporter activity in Caco-2 cells in a dose-dependent manner, and the expression of exogenous vitamin D receptor further stimulated the vitamin D receptor activity. Quercetin-like flavonoids such as kaempferol stimulated the vitamin D receptor activity in a manner similar to that seen with quercetin. Taken together, the data indicates that quercetin upregulates cytochrome P450 3A4 and multidrug resistance protein 1 expression in Caco-2 cells likely via a vitamin D receptor-dependent pathway.

Use of quercetin in animal feed: effects on the P-gp expression and pharmacokinetics of orally administrated enrofloxacin in chicken

“…In this study, Caco-2 cell line was firstly selected as an in vitro model for validating the effects of quercetin on P-gp expression at the transcriptional and translational level. These results established that quercetin is a potential inducer of P-gp mRNA/protein, which was consistent with some previous reports about flavonoids inducing the P-gp expression 15 , 24 , 25 . Therefore, the in vivo tests in chicken were undertaken.…”

“…It is reported that various flavonoids including quercetin regulated the P-gp expression through pregnane X receptor (PXR) and constitutive androstane receptor (CAR) 32 in human, and recently, it is also reported that quercetin upregulated the P-gp through vitamin D receptor (VDR) dependent pathway in Caco-2 cells 25 . It was previously demonstrated that the quercetin has potential to interact with multiple targets via judicious analysis using reverse docking methods 33 .…”

Role of vitamin D receptor in the regulation of CYP3A gene expression

“…Introduction of VDR siRNA suggested that the effects of quercetin on CYP3A4 required the normal functions of VDR in Caco-2 cells. Other quercetin-like flavonoids (kaempferol and berberine) of equal concentration and treatment duration resulted in similar effects on these genes 93 . The inductive effects of complementary and alternative medicines (CAM) on CYP3A4 through PXR- or CAR-mediated pathway has been elucidated 94 .…”

<p>Effect of Kaempferol on Tacrolimus-Induced Nephrotoxicity and Calcineurin B1 Expression Level in Animal Model</p>

“… 27 Another in vitro study on Caco-2 cells confirmed that three consecutive days of KMF and Quercetin treatment could induce a considerable increase in the mRNA expression for both P-gp and CYP3A4. 28 …”