Paeoniflorin and albiflorin regulate P-gp-mediated aconitine and hypaconitine transport through an Madin Darby canine kidney-multi drug resistance protein 1 cell model

Abstract

Aconitine and hypaconitine are the main active ingredients of Radix Aconiti, paeoniflorin and albiflorin are the primary components of Radix Paeoniae Alba. Both Radix Aconiti and Radix Paeoniae Alba are herbs that are commonly used in traditional Chinese medicine. This study sought to explore the mechanistic transport of aconitine and hypaconitine across MDCK-MDR1 cells and to assess the effect of paeoniflorin and albiflorin on aconitine and hypaconitine transmembrane transport as a potential attenuation mechanism. Drug cytotoxicity was tested via the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and transport studies were performed in both directions. The effects of drugs on P-gp ATPase activity, P-gp efflux function, MDR1 mRNA and P-gp expression were evaluated in MDCK-MDR1 cells. Aconitine and hypaconitine treatment with the verapamil could significantly decrease the efflux rate (ER). The ER of aconitine and hypaconitine were significantly increased with the coadministration of paeoniflorin and albiflorin, suggesting that paeoniflorin and albiflorin can promote the efflux of these two alkaloids. Aconitine and hypaconitine can induce P-gp enzymatic activity, inhibit P-gp-mediated efflux, and downregulate the expression of P-gp protein to produce cytotoxic effects. When treatment in combination with paeoniflorin and albiflorin, it could stimulated P-gp ATPase activity, increasing mRNA expression, enhance P-gp efflux function, and upregulate P-gp protein expression.