Effects of Polyphenols on P-Glycoprotein (ABCB1) Activity

Abstract

P-glycoprotein (Pgp, ABCB1) is a member of one of the largest families of active transporter proteins called ABC transporters. Thanks to its expression in tissues with barrier functions and its broad substrate spectrum, it is an important determinant of the absorption, metabolism and excretion of many drugs. Pgp and/or some other drug transporting ABC proteins (e.g., ABCG2, MRP1) are overexpressed in nearly all cancers and cancer stem cells by which cancer cells become resistant against many drugs. Thus, Pgp inhibition might be a strategy for fighting against drug-resistant cancer cells. Previous studies have shown that certain polyphenols interact with human Pgp. We tested the effect of 15 polyphenols of sour cherry origin on the basal and verapamil-stimulated ATPase activity of Pgp, calcein-AM and daunorubicin transport as well as on the conformation of Pgp using the conformation sensitive UIC2 mAb. We found that quercetin, quercetin-3-glucoside, narcissoside and ellagic acid inhibited the ATPase activity of Pgp and increased the accumulation of calcein and daunorubicin by Pgp-positive cells. Cyanidin-3O-sophoroside, catechin, naringenin, kuromanin and caffeic acid increased the ATPase activity of Pgp, while they had only a weaker effect on the intracellular accumulation of fluorescent Pgp substrates. Several tested polyphenols including epicatechin, trans-ferulic acid, oenin, malvin and chlorogenic acid were ineffective in all assays applied. Interestingly, catechin and epicatechin behave differently, although they are stereoisomers. We also investigated the effect of quercetin, naringenin and ellagic acid added in combination with verapamil on the transport activity of Pgp. In these experiments, we found that the transport inhibitory effect of the tested polyphenols and verapamil was additive or synergistic. Generally, our data demonstrate diverse interactions of the tested polyphenols with Pgp. Our results also call attention to the potential risks of drug–drug interactions (DDIs) associated with the consumption of dietary polyphenols concurrently with chemotherapy treatment involving Pgp substrate/inhibitor drugs.

Possible Side Effects of Polyphenols and Their Interactions with Medicines

“…On the other hand, the induction of P450 activity diminishes the duration of action of a drug by increasing its metabolic elimination, which is also an undesirable effect and may pose a serious risk [ 109 ]. In addition, polyphenols can also affect drug transport through their interaction with the drug transporters, e.g., P-glycoprotein belonging to ABC transporters [ 294 ], organic anion transporting polypeptides (OATPs), and organic cation transporters (OCTs) [ 293 , 295 ].…”

The Microstructure, Antibacterial and Antitumor Activities of Chitosan Oligosaccharides and Derivatives

“…One of the most common mechanisms of acquired drug resistance relies on drug efflux of cancer cells mediated by ATP binding box (ABC) transporters [85]. P-Glycoprotein (P-gp) is one of the major transporters that expels many drugs, reducing intracellular drug concentrations below effective cytotoxic thresholds [86][87][88].…”

Modern aspects of the use of natural polyphenols in tumor prevention and therapy

“…Several mechanisms of action have been identified for the chemopreventive action of polyphenols, including estrogenic/antiestrogen activity, antiproliferative activity, apoptosis induction, cell cycle inhibition, oxidation prevention, detoxification enzyme induction, regulation of the host immune system, and anti-inflammatory activity ( Singh et al, 2021a ; Bahrami et al, 2021 ; Weh et al, 2022 ) ( Figure 2 , Figure 3 and Figure 4 ). At the same time, polyphenols can affect the metabolism of pro-carcinogens and modulate the expression of cytochrome P450 enzymes involved in their activation into carcinogens.…”