Pulchinenosides from Pulsatilla Chinensis Increase P‐Glycoprotein Activity and Induce P‐Glycoprotein Expression

Abstract

Five pulchinenosides (pulchinenoside B3, pulchinenoside BD, pulchinenoside B7, pulchinenoside B10, and pulchinenoside B11) isolated from Pulsatilla chinensis (Bge) Regel saponins extract exhibited strong antitumor activities but poor gastrointestinal absorption properties. The enteric induction of P-glycoprotein (P-gp) is understood to restrict the oral bioavailability of some pharmaceutical compounds and lead to adverse drug reactions. Therefore, the present investigation was intended to delineate the impacts of pulchinenosides on cellular P-gp function and expression using Sf9 membrane vesicles and LS180 cells as a surrogate of human intestinal epithelial cells. Preliminary cytotoxic studies showed that 10 μM was an acceptable concentration for cytotoxicity and antiproliferation studies for all pulchinenosides using the alamarBlue assay. The cell cycle of LS180 cells detected by flow cytometry was not significantly influenced after 48 hours of coincubation with 10 μM of pulchinenosides. In the presence of pulchinenosides, the ATP-dependent transport of N-methyl-quinidine mediated by P-glycoprotein was stimulated significantly. The upregulation of P-glycoprotein and mRNA levels was found by Western blot and real-time PCR analysis in LS180 cells. Parallel changes indicate that all pulchinenosides are exposed to pulchinenosides-mediated transcriptional regulation. In conclusion, pulchinenosides could induce P-glycoprotein expression and directly increase its functional activity.

Approaches to minimize the effects of P‐glycoprotein in drug transport: A review

“…Although these studies have already been proven effec- polyacetylenes (Srivalli & Lakshmi, 2012;Abdallah et al, 2015;Zhou et al, 2004;Junco et al, 2013;Yu et al, 2016;Dewanjee et al, 2017;Peng et al, 2020). Pulchinenosides induced the P-gp and stimulated the ATP-dependent transport of N-methyl-quinidine (Liu et al, 2020).…”

“…However, several reports concerning the activity of various plant extracts and their constituents as P‐gp inhibitors; viz., anthraquinones, phenylbutanoids, phytosterols, cannabinoids, carotenoids, curcuminoids, volatile oils, sulfur compounds, and polyacetylenes (Srivalli & Lakshmi, 2012; Abdallah et al, 2015; Zhou et al, 2004; Junco et al, 2013; Yu et al, 2016; Dewanjee et al, 2017; Peng et al, 2020). Pulchinenosides induced the P‐gp and stimulated the ATP‐dependent transport of N‐methyl‐quinidine (Liu et al, 2020). Wutou‐Gancao herb and liquorice bioactive ingredients (liquiritigenin) enhanced the Cmax and AUC of Aconitine by inhibiting P‐gp (He et al, 2020).…”

“…(Wu & Fu, 2018; Genovese et al, 2017; Karthikeyan & Laxmanappa Hoti, 2015; Lopez & Martinez‐Luis, 2014; Wu et al, 2011; Palmeira et al, 2012; Sharom, 2007). Several examples listed in Table 1 along with corresponding chemical structures (Figure 2) identified as substrate, inhibitors, and inducers of P‐gp (USFDA, 2020; EMA, 2020; Amadi & Nwachukwu, 2020; Liu et al, 2020; Bikdeli et al, 2020; Kopecka et al, 2020; Elmeliegy, Vourvahis, et al, ; Atta et al, 2019; Maideen, 2019; Konieczny & Dorian, 2019; Fogli et al, 2019; Vranckx et al, 2018; Ledwitch & Roberts, 2017; Mealey & Fidel, 2015; Finch & Pillans, 2014; Srivalli & Lakshmi, 2012; Levin & Ellingrod, 2012; Hoosain et al, 2015). Verapamil enhanced the Irinotican mean area under the plasma concentration‐time curve (AUC) from 14.03 to 61.71 μg h/ml (Bansal et al, 2009).…”

Identification ofPulsatilla chinensis(Bge.) Regel and look‐alike species by UHPLC‐TOF‐MS using multivariate statistical analysis

“…It has been used to treat bacillary dysentery for thousands of years. Modern studies have shown that it has anti‐inflammatory, antibacterial, antioxidant, antitumor, and other pharmacological effects [1–15], leading to its application in proprietary Chinese medicine. Triterpenoid saponins were predominant biologically active constituents, and these were subcategorized into lupane and oleanane saponins on skeletal basis [16, 17].…”

“…It has been used to treat bacillary dysentery for thousands of years. Modern studies have shown that it has anti-inflammatory, Article Related Abbreviations: EMRT, exact mass retention time; OPLS-DA, orthogonal partial least square discriminant analysis; PCA, principal component analysis; RT, retention time antibacterial, antioxidant, antitumor, and other pharmacological effects [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15], leading to its application in proprietary Chinese medicine. Triterpenoid saponins were predominant biologically active constituents, and these were subcategorized into lupane and oleanane saponins on skeletal basis [16,17].…”