Berberine Upregulates P-Glycoprotein in Human Caco-2 Cells and in an Experimental Model of Colitis in the Rat via Activation of Nrf2-Dependent Mechanisms

Abstract

Downregulation of P-glycoprotein (P-gp) is implicated in the pathophysiology of inflammatory bowel disease (IBD). Berberine, a principal isoquinoline alkaloid extracted from species, has been reported to exhibit therapeutic potential in IBD. In this study, we used a dextran sulfate sodium (DSS)-induced colitis rat model to evaluate the effect of berberine on P-gp and explore its mechanism of action. Berberine treatment improved DSS-induced colitis symptoms, attenuated inflammatory markers (myeloperoxidase, tumor necrosis factor-, and interleukin-1 and -6), and enhanced P-gp expression in a dose-dependent manner. Although colonic expression of the P-gp-related nuclear receptor pregnane X receptor and transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) were downregulated in the colitis model, gene and protein expression analysis revealed that berberine treatment reversed only the downregulation of Nrf2. In vitro studies using Caco-2 cells showed that the multidrug resistance 1 () gene and P-gp protein were upregulated by berberine in a dose- and time-dependent manner. Significant upregulation of the gene by berberine was abrogated by Nrf2 silencing, indicating that the Nrf2-mediated pathway was responsible for this activation. Luciferase assays showed a dose-dependent increase in Nrf2 reporter gene activity after berberine treatment in Caco-2 cells, with a significant 2-fold elevation at 2.5M berberine, suggesting that berberine is a strong Nrf2 activator. These results indicate the possible involvement of Nrf2-mediated upregulation of P-gp in the therapeutic effect of berberine on colitis and highlight the potential of P-gp and/or Nrf2 as new therapeutic targets for IBD.

Inhibitory Effect of Berberine on Broiler P-glycoprotein Expression and Function: In Situ and In Vitro Studies

“…Our results are very similar to the finding that camptothecin (an isoquinoline alkaloid, like berberine) attenuates cytochrome P450 3A4 induction by blocking the activation of human PXR [23]. However, The results of this study are inconsistent with the recent data showing that berberine up-regulate P-gp through transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) but not through PXR when colitis occurs in rats [24]. This discrepancy is most likely due to the different regulatory pathways of P-gp between normal and pathologic systems.…”

Plant-Derived Alkaloids: The Promising Disease-Modifying Agents for Inflammatory Bowel Disease

“…Isoquinoline alkaloids are classes of medicinally active alkaloids formed from a precursor of 3,4-dihydroxytyramine (dopamine) linked to an aldehyde or ketone with multiple properties including antispasmodic, antimicrobial, antitumor, antifungal, anti-inflammatory, cholagogue, hepatoprotective, antiviral, amebicidal, and anti-oxidant activities (Iranshahy et al, 2014). Berberine ( 7 ), a well-known representative of this type of alkaloid mainly isolated from traditional Chinese medicines Coptis chinensis and Phellodendron chinense , has been reported to possess the ability to protect experimental colitis through regulating innate and adaptive immune responses, intestinal barrier function and the gut microbiota (Lee et al, 2010; Yan et al, 2012; Kawano et al, 2015; Li et al, 2015, 2016; Lv Z. et al, 2015; Zhang et al, 2017; Cui et al, 2018; Jing et al, 2018; Liu et al, 2018). Among these reports, Yan et al (2012) revealed that oral administration of berberine (100 mg/kg of body weight in mice) significantly ameliorated DSS-induced intestinal injury and colitis associated with decreasing the disruption of barrier function and apoptosis of colon epithelium, thus inhibiting the proinflammatory cytokine TNF-α, IFN-γ, KC, and IL-17 production of colonic macrophages and promoting the apoptosis of colonic macrophages through down-regulating the activation of MAPK and NF-κB (Yan et al, 2012).…”

“…Fecal transplantation from berberine-treated mice could relieve UC and regulate the Treg/Th17 balance. Further, using DSS-induced murine colitis, Jing et al (2018) investigated the effect of berberine on P-glycoprotein (P-gp), one of the most important proteins of the cell membrane that pumps harmful molecules out of the intestinal mucosa; the results revealed that berberine (10 and 40 mg/kg of body weight in mice, p.o.) could significantly ameliorate intestinal inflammation by enhancing P-gp expression, which is independent of nuclear factor erythroid 2-related factor 2 (Nrf2) activation.…”

Anti‑inflammatory mechanism of berberine on lipopolysaccharide‑induced IEC‑18 models based on comparative transcriptomics

“…BBr potently suppressed the inflammatory response in macrophages by inhibiting nF-κB signaling via sirtuin-1-dependent mechanisms (20). administration of BBr can notably ameliorate disease severity and restore the mucosal barrier homeostasis of patients with uc (21), and upregulate P-glycoprotein via activation of nuclear factor erythroid 2-related factor 2-dependent mechanisms to improve symptoms in patients with uc (22). BBr also inhibits inflammatory responses as well as T helper cell (Th)1/Th7 differentiation to ameliorate 2,4,6-Trinitrobenzenesulfonic acid solution (TnBS)-induced iBd (23).…”