Structure-activity relationship and mechanism of flavonoids on the inhibitory activity of P-glycoprotein (P-gp)-mediated transport of rhodamine123 and daunorubicin in P-gp overexpressed human mouth epidermal carcinoma (KB/MDR) cells. (September 2021)

• Record Type: Journal Article
• Authors: Fang, Yajing; Liang, Fuqiang; Xia, Mengmeng; Cao, Weiwei; Pan, Siyi; Wu, Ting; Xu, Xiaoyun
• Is Part Of: Food and chemical toxicology. Volume 155(2021)
• Publication Date: 2021-09
• Subjects: P-glycoprotein substrates -- Cellular uptake -- Flavonoids -- P-glycoprotein inhibitors -- KB/MDR cells -- Structure-activity relationship; ATP adenosine triphosphate -- CU cellular uptake -- DMSO dimethyl sulfoxide -- DNR daunomycin -- MDR multidrug resistance -- NBD nucleotide-binding domain -- PBS phosphate buffer solution -- P-gp P-glycoprotein -- RF reversal folds -- Rho rhodamine123 -- RIPA radio-immunoprecipitation assay -- SAR structure-activity relationship; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2021.112381
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: This study was aimed to investigate the inhibitory activity of flavonoids on P-glycoprotein (P-gp). Effects of 39 flavonoids on the cellular uptake (CU) of rhodamine123 (Rho) and daunomycin (DNR) were investigated in both parental KB and P-gp overexpressed KB/MDR cells. The inhibition mechanism of selected flavonoids was further investigated by measuring the ATPase activity and expression level of P-gp. Twelve flavonoids improved the uptake of Rho (↑RhoF ) and nineteen flavonoids increased the uptake of DNR (↑DNRF ) in KB/MDR cells with nine flavonoids overlapped. Structure-activity relationship (SAR) indicated that 8-OCH3, and 2′-OH have a negative effect on Rho and DNR transport. Whereas 5-OH, 5-OCH3, 6-OH, 7-OCH3, 3′-OH, and 4′-OH, are essential for inhibition of flavonoids on P-gp and reversing the resistance of Rho and DNR. Eleven selected flavonoids significantly induced the basal P-gp-ATPase activity but much lower than that induced by verapamil. Tangeretin, galangin, kaempferol, quercetin, and morin significantly reversed the ATPase activity stimulated by verapamil. Six of eleven flavonoids significantly decreased P-gp expression, whereas three flavonoids slightly increased P-gp expression. These results provide valuable information that flavonoids can effectively reverse multidrug resistance of P-gp-mediated transport of nutraceutical and drugs by co-administration. Graphical abstract: Image 1 Highlights: 39 flavonoids (Fs) were tested for improving Rho or DNR uptake in KB/MDR cells. 12 Fs improved Rho uptake and 19 Fs increased DNR uptake with 9 Fs overlapped. 5-OH, 5-OCH3, 6-OH, 7-OCH3, 3′-OH, and 4′-OH, are essential for inhibition on P-gp. Fs inhibited P-gp by decreasing its expression and inhibiting its ATPase activity.