Efflux transporters such as P-glycoprotein play an important role in email updates on NPS MedicineWise CPD activities and resources . This process affects their plasma and tissue concentrations and Drugs which induce or inhibit P-glycoprotein can interact with other drugs handled by the pump. P-glycoprotein 1 also known as multidrug resistance protein 1 (MDR1) or ATP- binding cassette Many drugs inhibit P-gp, typically incidentally rather than as their main to have a direct impact in the transporter's structural stability (in the nucleotide-binding . Elacridar & CP are other common Pgp inhibitors. The effects of P-gp on the distribution, metabolism and excretion of drugs P-gp activity, for example, decreases the intracellular concentration of cancer drugs, enabling bowel disease; however, this has not been observed by other researchers. This strongly suggests that P-gp transport at the intestinal and/or hepatic.
activity drug on and P-glycoprotein Effects transporters other
P-gp protein expression was analyzed by immunoblotting with C mouse monoclonal antibody. Cells were treated for 48 h followed by Western blot analysis for P-gp expression shown as column bars and uptake study for P-gp activity shown as lines.
The functional significance of the increase in P-gp expression was determined by evaluating the cellular uptake of P-gp substrate rhodamine following treatments with increasing concentrations of the compounds ranging from 2. Percent change in the accumulation of rhodamine was evaluated in the presence dashed bars and absence solid bars of verapamil, a specific P-gp inhibitor. The potencies of the compounds to up-regulate P-gp activity were estimated from the average of fold increase in P-gp activity.
Table 1 illustrates the in vitro potencies of the inducers to up-regulate P-gp activity as follows: However, unlike rifampicin that increased P-gp activity by 4. Fluorescence of secondary antibody against P-gp was located mainly on the cell membrane. The quantitative analysis of P-gp expressed in LS cells showed a significant increase in membrane P-gp expression of compound-treated cells compared to control.
For example, oleocanthal and cembratriene resulted in 9. Quantitative folds change in the P-gp expression were measured using ImageJ version 1. P-gp, an efflux transporter, is highly expressed in body tissues and can form a biological barrier against xenobiotic agents. Thus, it can be a major determinant of drug pharmacokinetic behavior and response.
Inhibition or induction of P-gp has been reported to be one of the causes of drug-drug interactions in animals and humans. Besides, it has been reported that natural products found in traditional medicine and dietary supplements can modulate P-gp activity Marchetti et al. Therefore, we aimed in this study to investigating the in vitro effect of bioactive natural plant products on P-gp expression and activity in LS human colon adenocarcinoma cell line Tom et al.
Rifampicin is a well established inducer of P-gp Ballent et al. Terpenes and phenolics are among the most abundant plant bioactive secondary metabolites Newman and Cragg, These bioactive natural products, which present in dietary supplements and food, have shown to provide potential therapeutic benefits.
Oleocanthal, a phenolic ester secoiridoid found in extra-virgin olive oil, is a key ingredient of the Mediterranean diet. It has a natural pain relief effect similar to ibuprofen, and exerts anti-inflammatory activity via inhibition of COX-1 and COX-2 activities Beauchamp et al.
Oleocanthal is widely believed to be useful for cancer Elnagar et al. On the other hand, cembratriene is a natural cembranoid diterpene found in the leaf and flower cuticular wax of most Nicotiana species Ferchmin et al. In rats, tobacco cembranoids were reported to block the expression of the behavioral sensitization to nicotine and inhibit neuronal acetylcholine receptors, suggesting a possible use for the treatment of nicotine addiction Ferchmin et al.
Similar to oleocanthal, cembranoids have also an anticancer activity and were reported to inhibit tumorigenesis Saito et al. It exhibits significant health benefits including anticancer Shah and Sylvester, , anticholesterolemic Song and DeBose-Boyd, , and potent antioxidant activities Tomeo et al. Finally, asiatic acid is a pentacyclic triterpenoid derived from the tropical medicinal plants Centella asiatica and Melaleuca ericifolia Hsu et al.
Several studies have also shown asiatic acid to be cytotoxic in a wide variety of cancer cell lines, including breast cancer, melanoma and myeloma Hsu et al. In the literature, few studies have evaluated the exposure consequences of the crude extract of cembratriene tobacco smoke extract Pan et al.
For example, Pan et al. The authors reported that the efflux of rhodamine was reduced in a concentration-dependent manner. However, these authors did not identify the specific compounds in the tobacco smoke extract responsible for such effect Pan et al.
Similarly, taraxastane-type triterpenes isolated from Euphorbia lagascae and E. In addition, Zhou et al. Quantitative analysis of P-gp expression obtained from immunofluorescence images was higher than those obtained from Western blotting, which could be related to the method sensitivity; overall, the results from both procedures were parallel Figs.
In addition, consistent with the expression studies, the activity studies demonstrated an increase in P-gp activity Figs. The functionality of P-gp in these cells was demonstrated by rhodamine accumulation, which decreased by compounds treatment and increased by P-gp inhibition with verapamil, a specific competitive inhibitor for P-gp and is commonly used to evaluate the functionality of P-gp efflux transporter Pham et al.
The P-gp inducer rifampicin significantly altered the pharmacokinetics of both drugs. Besides, following 23 days of rifampicin treatment, Greiner et al. P-gp and CYP3A are regulated via PXR and act coordinately at the intestinal barrier in determining drugs disposition, thus the modulation of intestinal P-gp, by inhibition or induction, is expected to modulate CYP3A as in the case of rifampicin Pfrunder et al.
Thus, the above data would not demonstrate the tested compounds as CYP3A up-regulators. However, their potential to up-regulate CYP3A is very likely, which may present an additional mechanism for food-drug interactions that requires further consideration. In conclusion, our data have confirmed the ability of the bioactive natural compounds examined in this study to in vitro up-regulate both P-gp activity and expression.
Thus, concomitant use of these bioactive natural products with P-gp substrate drugs might induce potential drug interactions and interfere with their pharmacokinetics and therapeutic effects. The tobacco-derived cembratriene was the most potent while the triterpene asiatic acid was the least. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institute of Health.
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Author manuscript; available in PMC Nov 1. Abuznait , Hisham Qosa , Nicholas D. Sylvester , Khalid A. El Sayed , and Amal Kaddoumi. Author information Copyright and License information Disclaimer. Corresponding Author Amal Kaddoumi, Ph.
The publisher's final edited version of this article is available at Food Chem Toxicol. See other articles in PMC that cite the published article. Abstract The effect of bioactive plant natural products on the expression and functional activity of P-glycoprotein P-gp is poorly understood. Open in a separate window. Methods and materials 2. Discussion P-gp, an efflux transporter, is highly expressed in body tissues and can form a biological barrier against xenobiotic agents.
Footnotes Conflict of interest The authors declare that there are no conflicts of interest. Antiproliferative triterpenes from Melaleuca ericifolia. Up-regulation of P-glycoprotein reduces intracellular accumulation of beta amyloid: Exposure of LS cells to drugs of diverse physicochemical and therapeutic properties up-regulates P-glycoprotein expression and activity. J Pharm Pharmaceut Sci. Natural products and adverse drug interactions.
Pretreatment with the inducers rifampicin and phenobarbital alters ivermectin gastrointestinal disposition. J Vet Pharmacol Ther. Effects of flavonols on P-glycoprotein activity in cultured rat hepatocytes.
Mediterranean diet, olive oil and cancer. The effect of food components on the absorption of P-gp substrates: Multidrug resistance modulation and apoptosis induction of cancer cells by terpenic compounds isolated from Euphorbia species.
Biocatalytic and semisynthetic optimization of the anti-invasive tobacco 1 S ,2 E ,4 R ,6 R ,7 E ,11 E -2,7,cembratriene-4,6-diol. After year , MicroRNAs miRNAs are identified as new players in regulating the expression of P-gp in both transcriptional and post-transcriptional levels. Some members of miRNAs decrease the expression of P-gp. For example, miRa up-regulates P-gp expression by suppressing Raf kinase inhibitor protein RKIP ;  alternatively, miRa can also directly bind to the promoter of P-gp gene, which works in a similar way with the mechanism of action of transcriptional factors.
The expression of P-gp is also regulated by post-translational events, such as post-transcriptional modification , degradation , and intracellular trafficking of P-gp. Pim-1 protects P-gp from ubiquitination and the following degradation in proteasome. Rab4 down-regulates the exocytotic trafficking of P-gp from intracellular compartments to cell membrane, and therefore decreases the functional P-gp level on cell membrane.
Some common pharmacological inhibitors of P-glycoprotein include: Common pharmacological inducers of P-glycoprotein include carbamazepine , dexamethasone , doxorubicin , nefazodone , phenobarbital , phenytoin , prazocin , rifampin , St. Johns wort , tenofovir , tipranavir , trazodone , and vinblastine.
Substrates of P-glycoprotein are susceptible to changes in pharmacokinetics due to drug interactions with P-gp inhibitors or inducers. Some of these substrates include colchicine , cyclosporine , dabigatran  , digoxin , diltiazem  , fexofenadine , indinavir , morphine , and sirolimus. Altered P-gp function has also been linked to inflammatory bowel diseases IBD ,  however, due to its ambivalent effects in intestinal inflammation many questions remain so far unanswered.
P-gp efflux activity is capable of lowering intracellular concentrations of otherwise beneficial compounds, such as chemotherapeutics and other medications, to sub-therapeutic levels. Consequently, P-gp overexpression is one of the main mechanisms behind decreased intracellular drug accumulation and development of multidrug resistance in human multidrug-resistant MDR cancers.
P-gp was first characterized in P-gp was shown to be responsible for conferring multidrug resistance upon mutant cultured cancer cells that had developed resistance to cytotoxic drugs. The first structure of human P-gp was solved in , with the protein in its ATP-bound, outward-facing conformation. Radioactive verapamil can be used for measuring P-gp function with positron emission tomography. P-gp is also used to differentiate transitional B cells from naive B cells.
Dyes such as rhodamine and MitoTracker dyes from Invitrogen can be used to make this differentiation. This article incorporates text from the United States National Library of Medicine , which is in the public domain. From Wikipedia, the free encyclopedia. Chromosome 5 mouse . This section is empty.
You can help by adding to it. The Journal of Biological Chemistry. Archived from the original on Journal of Pharmaceutical Sciences. Update of the Literature". Atlas of Genetics and Cytogenetics in Oncology and Haematology. Alternating access with a twist". Journal of Chemical Theory and Computation. Advanced Drug Delivery Reviews.
Table of Substrates, Inhibitors and Inducers". Cancer Chemotherapy and Pharmacology. Digestive Diseases and Sciences. Biochimica et Biophysica Acta. International Journal of Cancer.
The Final Frontier for Drug Interactions". Brazilian Journal of Pharmaceutical Sciences. Appendix A " PDF. More questions than answers". World Journal of Gastroenterology.
(1)Department of Drug Metabolism, Merck Research Laboratories, West Point, Because of its localisation, P-glycoprotein appears to have a greater impact on This is because P-glycoprotein transport activity becomes saturated by high On the other hand, there are significant species differences in P-glycoprotein. Recently, Roberts and Goralski  critically reviewed the effects of inflammation or infection on P-glycoprotein activity and expression in brain. P-glycoprotein (ABCB1) is one of the most extensively studied transporters On the other hand, the inhibition of the intestinal P-glycoprotein activity can lead to Interactions; Humans; Intestinal Mucosa/metabolism*; Intestines/drug effects.