Inhibition of P-Glycoprotein Mediated Efflux in Caco-2 Cells by Phytic Acid

Abstract

Phytic acid (IP6) is a natural phosphorylated inositol, which is abundantly present in most cereal grains and seeds. This study investigated the effects of IP6 regulation on P-glycoprotein (P-gp) and its potential mechanisms using in situ and in vitro models. The effective permeability of the typical P-gp substrate rhodamine 123 (R123) in colon was significantly increased from (1.69 ± 0.22) × 10 cm/s in the control group to (3.39 ± 0.417) × 10 cm/s (p < 0.01) in the 3.5 mM IP6 group. Additionally, IP6 can concentration-dependently decrease the R123 efflux ratio in both Caco-2 and MDCK II-MDR1 cell monolayers and increase intracellular R123 accumulation in Caco-2 cells. Furthermore, IP6 noncompetitively inhibited P-gp by impacting R123 efflux kinetics. The noncompetitive inhibition of P-gp by IP6 was likely due to decreases in P-gp ATPase activity and P-gp molecular conformational changes induced by IP6. In summary, IP6 is a promising P-gp inhibitor candidate.

Establishment and Use of Human Mouth Epidermal Carcinoma (KB) Cells Overexpressing P-Glycoprotein To Characterize Structure Requirements for Flavonoids Transported by the Efflux Transporter

“…5 P-gp is extensively expressed at the apical side of epithelial cells in the kidneys, liver, and especially intestine. P-gp acts as barrier and protects cells from exogenous xenobiotics by mediating efflux of compounds across the apical membrane of enterocytes, 7 thus attenuating absorption and facilitating excretion of its substrates.…”

A Review of Phytic Acid Sources, Obtention, and Applications

“…The importance of phytic acid as a dietary component is not yet fully clarified, although its protective effects against cancer have been widely studied and proven, using cell lines, such as hepatocellular carcinoma (HepG2) and Caco-2 cells, and in vivo studies mainly performed with rats. [9,[83][84][85] In the first case, after a 48-hour-treatment, HepG2 viability was 23.8% in succinate dehydrogenase activity (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT)) assay, and 32.4% in lactate dehydrogenase (LDH) assay, at 3.5 mM phytic acid. [85] For Caco-2 cells, the phytic acid decreased the effective permeability of the typical P-glycoprotein (P-gp) substrate rhodamine 123 (R123) by 50% in the colon, also at the 3.5 mM phytic acid.…”

“…[85] For Caco-2 cells, the phytic acid decreased the effective permeability of the typical P-glycoprotein (P-gp) substrate rhodamine 123 (R123) by 50% in the colon, also at the 3.5 mM phytic acid. [84] Khatiwada et al ( 2006) [86] studied the effect of phytic acid and inositol on the induced colon tumor reduction in male rats. The results showed that 2 g 100 mL −1 phytic acid added to drinking water significantly reduced the occurrence of colon tumor in rats.…”

QTMP, a Novel Thiourea Polymer, Causes DNA Damage to Exert Anticancer Activity and Overcome Multidrug Resistance in Colorectal Cancer Cells

“…Notably, SW480, HCT116 and Caco2 cells are commonly used cell culture models for the study of CRC in vitro (3,25). Caco2 cells express high levels of P-gp protein, and these cells are naturally multidrug-resistant (25,31,32). The IC 50 values of QTMP in SW480, HCT116 and Caco2 cells were 4.73 ± 1.12, 5.66 ± 1.32 and 6.14 ± 1.45 mg/ml, respectively, indicating only slight differences in the IC 50 values of QTMP in these CRC cell lines (Table 2).…”