Down-regulation of P-gp expression and function after Mulberroside A treatment: potential role of protein kinase C and NF-kappa B.

P-Glycoprotein (P-gp) plays a major role in drug-drug and herb-drug interactions. Mulberroside A (Mul A) is one of the main bioactive constituents of Sangbaipi, the dried root-bark of Morus alba L. (white mulberry), which is officially listed in the Chinese Pharmacopoeia. In the present study, we investigated the effect of Mul A treatment on mRNA expression and protein expression of P-gp in the Caco-2 cells by real-time qPCR and Western blot analysis. The effect of Mul A treatment on the function of P-gp in vitro and in vivo was assessed by Rho123 transport assay and a pharmacokinetic study. The potential roles of protein kinase C (PKC) and nuclear factor kappa B (NF-κB) in the expression regulation of P-gp after Mul A treatment were also investigated. The results revealed that Mul A treatment significantly decreased the mRNA and protein expression of P-gp in Caco-2 cells after treatment with Mul A (5-20 μM). Furthermore, Mul A treatment displayed apparently inhibitory effect on the function of P-gp both in vitro and in vivo. In addition, activation of PKC activity and NF-κB nuclear translocation were observed in the presence of Mul A, which suggested that PKC and NF-κB might play crucial roles in Mul A-induced suppression of P-gp. Our study demonstrated that Mul A treatment could down-regulate P-gp expression and function accompanied by the activation of PKC and NF-κB, and this should be taken into consideration in potential herb-drug interactions when Mul A or M. alba are co-administered with other drugs transported by P-gp.