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Review
. 2017 May 25;22(6):871.
doi: 10.3390/molecules22060871.

Natural Products as Alternative Choices for P-Glycoprotein (P-gp) Inhibition

Saikat Dewanjee  1 , Tarun K Dua  2 , Niloy Bhattacharjee  3 , Anup Das  4 , Moumita Gangopadhyay  5 , Ritu Khanra  6 , Swarnalata Joardar  7 , Muhammad Riaz  8 , Vincenzo De Feo  9 , Muhammad Zia-Ul-Haq  10
Affiliations
Review

Natural Products as Alternative Choices for P-Glycoprotein (P-gp) Inhibition

Saikat Dewanjee et al. Molecules. .

Abstract

Multidrug resistance (MDR) is regarded as one of the bottlenecks of successful clinical treatment for numerous chemotherapeutic agents. Multiple key regulators are alleged to be responsible for MDR and making the treatment regimens ineffective. In this review, we discuss MDR in relation to P-glycoprotein (P-gp) and its down-regulation by natural bioactive molecules. P-gp, a unique ATP-dependent membrane transport protein, is one of those key regulators which are present in the lining of the colon, endothelial cells of the blood brain barrier (BBB), bile duct, adrenal gland, kidney tubules, small intestine, pancreatic ducts and in many other tissues like heart, lungs, spleen, skeletal muscles, etc. Due to its diverse tissue distribution, P-gp is a novel protective barrier to stop the intake of xenobiotics into the human body. Over-expression of P-gp leads to decreased intracellular accretion of many chemotherapeutic agents thus assisting in the development of MDR. Eventually, the effectiveness of these drugs is decreased. P-gp inhibitors act by altering intracellular ATP levels which are the source of energy and/or by affecting membrane contours to increase permeability. However, the use of synthetic inhibitors is known to cause serious toxicities. For this reason, the search for more potent and less toxic P-gp inhibitors of natural origin is underway. The present review aims to recapitulate the research findings on bioactive constituents of natural origin with P-gp inhibition characteristics. Natural bioactive constituents with P-gp modulating effects offer great potential for semi-synthetic modification to produce new scaffolds which could serve as valuable investigative tools to recognize the function of complex ABC transporters apart from evading the systemic toxicities shown by synthetic counterparts. Despite the many published scientific findings encompassing P-gp inhibitors, however, this article stand alones because it provides a vivid picture to the readers pertaining to Pgp inhibitors obtained from natural sources coupled with their mode of action and structures. It provides first-hand information to the scientists working in the field of drug discovery to further synthesise and discover new P-gp inhibitors with less toxicity and more efficacies.

Keywords: ABC transporters; P-glycoprotein (P-gp); P-gp inhibitors; chemotherapy; multi drug resistance (MDR); xenobiotics.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Basic structures of different types of P-gp transporters [2].
Figure 2
Figure 2
Overview of P-gp functional expressions throughout the body. Black lines indicate the location of ABCB1. Small arrows indicate the direction of ABCB1-mediated transport [9,10,22,23,24,25,26].
Figure 3
Figure 3
Schematic diagram representing different types of drug transporters present in microorganisms [27,28,29,30,31,32,33].
Figure 4
Figure 4
Schematic diagrams representing: (A) Structure of drug transporting P-gp; (B) drug binding pocket of P-gp; (C) drug binding pocket of P-gp surrounded by TMs [2,35,36,37,38,39,40,41,42].
Figure 5
Figure 5
Different functional models of P-gp induced MDR [46,47,48].
Figure 6
Figure 6
Schematic diagram represents P-gp efflux kinetics [49].
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
Figure 7
Figure 7
The structures of natural P-gp inhibitors mentioned in Table 3.
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