Herbal Modulation of P-Glycoprotein

Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
Drug Metabolism Reviews (Impact Factor: 5.36). 03/2004; 36(1):57-104. DOI: 10.1081/DMR-120028427
Source: PubMed


P-glycoprotein (Pgp) is a 170 kDa phosphorylated glycoprotein encoded by human MDR1 gene. It is responsible for the systemic disposition of numerous structurally and pharmacologically unrelated lipophilic and amphipathic drugs, carcinogens, toxins, and other xenobiotics in many organs, such as the intestine, liver, kidney, and brain. Like cytochrome P450s (CYP3A4), Pgp is vulnerable to inhibition, activation, or induction by herbal constituents. This was demonstrated by using an ATPase assay, purified Pgp protein or intact Pgp-expressing cells, and proper probe substrates and inhibitors. Curcumin, ginsenosides, piperine, some catechins from green tea, and silymarin from milk thistle were found to be inhibitors of Pgp, while some catechins from green tea increased Pgp-mediated drug transport by heterotropic allosteric mechanism, and St. John's wort induced the intestinal expression of Pgp in vitro and in vivo. Some components (e.g., bergamottin and quercetin) from grapefruit juice were reported to modulate Pgp activity. Many of these herbal constituents, in particular flavonoids, were reported to modulate Pgp by directly interacting with the vicinal ATP-binding site, the steroid-binding site, or the substrate-binding site. Some herbal constituents (e.g., hyperforin and kava) were shown to activate pregnane X receptor, an orphan nuclear receptor acting as a key regulator of MDR1 and many other genes. The inhibition of Pgp by herbal constituents may provide a novel approach for reversing multidrug resistance in tumor cells, whereas the stimulation of Pgp expression or activity has implication for chemoprotective enhancement by herbal medicines. Certain natural flavonols (e.g., kaempferol, quercetin, and galangin) are potent stimulators of the Pgp-mediated efflux of 7,12-dimethylbenz(a)-anthracene (a carcinogen). The modulation of Pgp activity and expression by these herb constituents may result in altered absorption and bioavailability of drugs that are Pgp substrates. This is exemplified by increased oral bioavailability of phenytoin and rifampin by piperine and decreased bioavailability of indinavir, tacrolimus, cyclosporine, digoxin, and fexofenadine by coadministered St. John's wort. However, many of these drugs are also substrates of CYP3A4. Thus, the modulation of intestinal Pgp and CYP3A4 represents an important mechanism for many clinically important herb-drug interactions. Further studies are needed to explore the relative role of Pgp and CYP3A4 modulation by herbs and the mechanism for the interplay of these two important proteins in herb-drug interactions.

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    • "In contrast to inhibitors that bind the N-terminus, novobiocin derivatives that target the C-terminal domain slow the growth of cancer cells and promote degradation of HSP90 clients without inducing the heat shock response, which is an important and somewhat unexpected distinction [80]. Other non-ATP-competitive HSP90 inhibitors are known, but most are non-selective, which limits their in vivo use; examples include epigallocatechin gallate [81] (inhibits several nonchaperone targets [82] [83] [84] [85] [86]), cisplatin [87] (damages DNA [88]), and silybin [89] (inhibits P-glycoprotein [90] and cytochrome P450 [91]). A particularly interesting class of small molecules is capable of modulating co-chaperone access to the EEVD motif in the HSP90 C-terminus. "
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    Journal of Molecular Biology 05/2015; 427(18). DOI:10.1016/j.jmb.2015.05.010 · 4.33 Impact Factor
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    • "The amount of berberine capable of crossing enterocytes seems to be reduced by about 90% by P-gp, and this suggests that either the use of a potential P-gp inhibitor21 or a chemical modification of berberine that would allow it to overcome P-gp antagonism22 might enhance its poor oral bioavailability, thus increasing its clinical effectiveness. Among the potential P-gp inhibitors, silymarin (derived from Silybum marianum), a herbal drug traditionally used as a liver protectant, could be considered a good candidate, owing to its very poor oral bioavailability and very high safety profile.23 We therefore decided to test the clinical role played by silymarin when added to berberine in the treatment of glycemic and lipid alterations in patients with T2DM. "
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    Clinical Pharmacology: Advances and Applications 11/2013; 5:167-174. DOI:10.2147/CPAA.S54308
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    • "The mechanisms by which β-CD and HP-β-CD inhibit Pgp activity may be different from that of other Pgp inhibitors, such as cyclosporine A, quinidine, and verapamil.43 Pgp recognizes many compounds as substrates, and tends to have a high affinity with hydrophobic and positively charged compounds at a certain physiological pH.44 β-CD and HP-β-CD do not appear to be substrates of Pgp because they are both hydrophilic and are electrically neutral cyclic oligosaccharides with a relatively high molecular weight.45 Furthermore, β-CD and HP-β-CD should not compete with Pgp substrates because of their lack of cell permeability.27 "
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