Berberine and berberrubine promote the expression of CYP3A4 via enhancing the binding of nuclear receptor PXR

Berberine is currently co-administered with statins in clinical practice for hyperlipidemia management. This study aimed to investigate the effects of berberine and berberrubine on CYP3A4 expression and the regulatory mechanism. Using rifampicin as a positive control group, HepG2 cells were treated with different concentrations of berberine and berberrubine. Q-PCR was employed to detect the expression levels of CYP3A4 mRNA in response to the drugs, and Western blot was utilized to determine the expression of CYP3A4 and PXR proteins. Dual luciferase reporter gene assay and RNA interference technology were used to silence PXR to explore the mechanism of berberine and berberrubine regulation of CYP3A4. Compared with the blank control group, both berberine and berberrubine could induce CYP3A4 mRNA expression in a concentration-dependent manner (P < 0.05). After treatment with 50 µM berberine and 60 µM berbamine for 48 h, the expression of CYP3A4 in HepG 2 cells was increased by 2.5 and 2.7 times, respectively. Berberine (10 ~ 50 µM) and berberrubine (15 ~ 60 µM) could upregulate the expression of PXR nuclear protein in a dose-dependent manner. Berberine and berbamine at different concentrations significantly upregulated the activity of the dual luciferase constructed based on PXR (P < 0.05), while silencing PXR reduced the inductive effects of berberine and berbamine on CYP3A4. Berberine and berbamine at different concentrations significantly upregulated the activity of the dual luciferase constructed based on PXR (P < 0.05), while silencing PXR reduced the inductive effects of berberine and berbamine on CYP3A4. Berberine and berberrubine can promote the expression of CYP3A4 protein in HepG2 cells by inducing the nuclear receptor PXR to bind to the promoter of CYP3A4.