The effect of herbal materials on the p-glycoprotein activity and function

Open access


P-glycoprotein (P-gp) encoded by the MDR1 (multidrug resistance 1) gene is ATP-dependent transporting protein which is localizated in the cell membrane. P-gp is expressed mainly in organs with the secretory functions and its physiological role concerns tissue protection against xenobiotics. P-glycoprotein is involved in the permeability barriers of the blood-brain, blood-placenta directly protecting these organs. It participates in the transport of many drugs and other xenobiotics affecting their absorption, distribution, metabolism and excretion. The high P-gp activity in the cell membranes of cancer tissue is a major cause of lack of effectiveness of chemotherapy. Hence, the methods which could increase the sensibility of these pathological cells to cytostatics are still being searched. In the experimental studies it was shown that natural plant substances may have an effect on the expression level and activity of P-glycoprotein. Hypericum perforatum, Ginkgo biloba and Camellia sinensis increase P-gp activity while curcumin from Curcuma longa, piperine and silymarin inhibit this protein. Taking into account a wide substrate spectrum of P-gp, application of our knowledge on interactions of herbals and synthetic drugs should be considered in order to improve drug impact on different tissues.

1. Loo TW, Bartlett MC, Clarke DM. Transmembrane segment 1 of human P-glycoprotein contributes to the drug-binding pocket. Biochem J 2006; 396:537-545.

2. Loo TW, Bartlett MC, Clarke DM. Transmembrane segment 7 of human P-glycoprotein forms part of the drug-binding pocket. Biochem J 2006; 399:351-359.

3. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM. P-glycoprotein: from genomics to mechanism. ONC 2003; 22:7468-7485.

4. Eichhorn T, Efferth T. P-glycoprotein and its inhibition in tumors by phytochemicals derived from Chinese herbs. J Ethnopharmacol 2012; 141:557-570.

5. Kozłowska-Rup D, Czekaj P. Barierowa rola białek nadrodziny ABC w łożysku ludzkim. Ginekol Pol 2011; 82:56-63.

6. Schinkel AH, Smit JJM, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994; 77:491-502.

7. Behravan J, Piquette-Miller M. Drug transport across the placenta, role of the ABC drug efflux transporters. Expert Opin Drug Metab Toxicol 2007; 3:819-830.

8. Zhou SF. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica 2008; 38:802-832.

9. Kim RB, Fromm MF, Wandel C, Leake B, Wood AJ, Roden DM. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 1998; 101:289-294.

10. Del Poeta G, Venditti A, Aronica G, Stasi R, Cox MC, Buccisano F. P-glycoprotein expression in de novo acute myeloid leukemia. Leuk Lymphoma 1997; 27:257-274.

11. Guerci A, Merlin JL, Missoum N, Feldmann L, Marchal S, Witz F et al. Predictive value for treatment outcome in acute myeloid leukemia of cellular daunorubicin accumulation and P-glycoprotein expression simoultanously determined by flow cytometry. Blood J 1995; 85:2147-53.

12. Liu YY, Han TY, Giuliano AE, Cabot MC. Ceramide glycosylation potentiates cellular multidrug resistance. FASEB J 2001; 15:719-730.

13. Watts GS, Futscher BW, Isett R, Gleason-Guzman M, Kunkel MW, Salmon SE. cDNA microarray analysis of multidrug resistance: doxorubicin selection produces multiple defects in apoptosis signaling pathways. J Pharmacol Exp Ther 2001; 299:434-41.

14. Droździk M, Białecka M, Myśliwiec K, Honczarenko K, Stankiewicz J, Sych Z. Polymorphism in the P-glycoprotein drug transporter MDR1 gene: a possible link between environmental and genetic factors in Parkinson's disease. Pharmacogenetic 2003; 13:259-263.

15. Schwab M, Schaeffeler E, Marx C, Fromm MF, Kaskas B, Metzler J et al. Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis. Gastroenterology 2003; 124:26-33.

16. Jeziorna M, Klimowicz A, Bielecka-Grzela S. The influence of P-glycoprotein and certain cytochrome P-450 isoenzymes on antimycotic azoles. Post Dermatol Alergol 2009; 6:533-538.

17. Roberts RL, Joyce PR, Mulder RT, Begg EJ, Kennedy MA. A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression. Pharmacogenomics 2002; 2:191-196.

18. Fellay J, Marzolini C, Meaden ER, Back DJ, Buclin T, Chave JP et al. Swiss HIV Cohort Study. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 2002; 359:30-36.

19. Rapposelli S, Digiacomo M, Balsamo A. P-gp transporter and its role in neurodegenerative diseases. Curr Top Med Chem 2009; 9:209-17.

20. Sikic I. Modulation of multidrug resistance: at the threshold. J Clin Oncol 1993; 11:1629-1635.

21. Kasper S, Gastpar M, Möller HJ, Müller WE, Volz HP, Dienel A et al. Better tolerability of St. John‘s wort extract WS 5570 compared to treatment with SSRIs: a reanalysis of data from controlled clinical trials in acute major depression. Int Clin Psychopharmacol 2010; 25:204-13.

22. Linde K, Berner MM, Kriston L. St John’s wort for major depression. Coch Database Syst Rev 2008; 8:CD000448.

23. Obach RS. Inhibition of human cytochrome P450 enzymes by constituents of St. John’s wort, an herbal preparation used in treatment of depression. J Pharmacol Exp Ther 2000; 294:88-95.

24. Bilia AR, Gallori S, Vincieri FF. St. John’s wort and depression: efficacy, safety and tolerability - an update. Life Sci 2002; 70:3077-96.

25. Calapai G, Crupi A, Firenzuoli F et al. Serotonin, norepinephrine and dopamine involvement in the antidepressant action of Hypericum perforatum. Pharmacopsych 2001; 34:45-9.

26. Wang Z, Hamman MA, Huang SM, Lesko LJ, Hall SD. Effect of St John‘s wort on the pharmacokinetics of fexofenadine. Clin Pharmacol Ther 2002; 71:414-20.

27. Rengelshausen J, Banfield M, Riedel KD, Burhenne J, Weiss J, Thomsen T et al. Opposite effects of short-term and long-term St John‘s wort intake on voriconazole pharmacokinetics. Clin Pharmacol Ther 2005; 78: 25-33.

28. Dürr D, Stieger B, Kullak-Ublick GA, Rentsch KM, Steinert HC, Meier PJ et al. St John‘s Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther 2000; 68:598-604.

29. Bauer S, Störmer E, Johne A, Krüger H, Budde K, Neumayer HH et al. Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John‘s wort in renal transplant patients. Br J Clin Pharmacol 2003; 55:203-11.

30. Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM et al. St. John‘s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 2000; 97:7500-2.

31. Suhaimi H, Ahmad FB, Friberg SE. Curcumin in a model skin lotion formulation. J Pharm Sci 1995; 84:376-80.

32. Nagabhushan M, Bhide SV. Nonmutagenicity of curcumin and its antimutagenic action versus chili and capsaicin. Nutr Cancer 1986; 8:201-10.

33. Limtrakul P, Anuchapreeda S, Lipigorngoson S, Dunn FW. Inhibition of carcinogen induced c-Ha-ras and c-fos proto-oncogenes expression by dietary curcumin. BMC Cancer 2001; 1:1-7.

34. Asai A, Miyazawa T. Dietary curcuminoids prevent high-fat diet induced lipid accumulation in rat liver and epididymal adipose tissue. J Nutr 2001; 131:2932-5.

35. Suryanarayana P, Krishnaswamy K, Reddy GB. Effect of curcumin on galactose-induced cataractogenesis in rats. Mol Vis 2003; 9:223-30.

36. Tang XQ, Bi H, Feng JQ, Cao JG. Effect of curcumin on multidrug resistance in resistant human gastric carcinoma cell line SGC7901/VCR. Acta Pharmacol Sin 2005; 26:1009-16.

37. Pallis M, Russell N. P-glycoprotein plays a drug-efflux-independent role in augmenting cell survival in acute myeloblastic leukemia and is associated with modulation of a sphingomyelin-ceramide apoptotic pathway. Blood 2000; 95:2897-2904.

38. Bajad S, Bedi KL, Singla AK et al. Antidiarrhoeal activity of piperine in mice. Planta Med 2001; 67:284-7.

39. Lin Z, Hoult JR, Bennett DC et al. Stimulation of mouse melanocyte proliferation by Piper nigrum fruit extract and its main alkaloid, piperine. Planta Med 1999; 65:600-3.

40. Zutshi RK, Singh R, Zutshi U et al. Influence of piperine on rifampicin blood levels in patients of pulmonary tuberculosis. J Assoc Physicians India 1985; 33:223-4.

41. Bano G, Raina RK, Zutshi U, Bedi KL, Johri RK, Sharma SC. Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers. Eur J Clin Pharmacol 1991; 41:615-7.

42. Li S, Lei Y, Jia Y, Li N, Wink M, Ma Y. Piperine, a piperidine alkaloid from Piper nigrum re-sensitizes P-gp, MRP1 and BCRP dependent multidrug resistant cancer cells. Phytomed 2011; 19:83-7.

43. Wu JW, Lin LC, Tsai TH. Drug-drug interactions of sylimarin on the perspective of pharmacokinetics. J Ethnopharmacol 2009; 121:185-93.

44. Dixit N, Baboota S, Kohli K, Ahmad S, Ali J. Silymarin: A review of pharmacological aspects and bioavailability enhancement approaches. Indian J Pharmacol 2007; 39:172-9

45. Zhang S, Morris ME. Effects of the flavonoids biochanin A and sylimarin on P-glycoprotein mediated transport of digoxin and vinblastine in human intestinal Caco-2 cells. Pharm Res 2003; 20:1184-91.

46. Gurley BJ, Barone GW, Williams DK et al. Effect of milk thistle (Sylibum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos 2006; 34:69-74.

47. Li L, Stanton JD, Tolson AH, Luo Y, Wang H. Bioactive terpenoids and flavonoids from Ginkgo biloba extract induce the expression of hepatic drug-metabolizing enzymes through pregnane X receptor, constitutive androstane receptor, and aryl hydrocarbon receptor-mediated pathways. Pharm Res 2009; 26:872-82.

48. Yang CY, Chao PD, Hou YC et al. Marked decrease of cyclosporine bioavailability caused by coadministration of ginkgo and onion in rats. Food Chem Toxicol 2006; 44:1572-8.

49. Wang E, Barecki-Roach M, Johnson WW. Elevation of P-glycoprotein function by a catechin in green tea. Biochem Biophys Res Commun 2002; 297:412-8.

50. Lin HL, Liu TY, Lui WY, Chi CW. Up-regulation of multidrug resistance transporter expression by berberine in human and murine hepatoma cells. BJC 1999; 85:1937-1942.

51. Li GH, Liu MX, Sun FJ, Wang N, Yin GP, Li XJ et al. The effect of tetrandrine on the expression of the P170, LRP and TOPO II in S180s tumor cell induced by chemotherapy in the mice with acquired multidrug resistance. Zhongguo Zhong Yao Za Zhi 2005; 30:1280-1282.

52. Cao J, Chen X, Liang J, Yu XQ, Xu AL, Chan E et al. Role of P-glycoprotein in the intestinal absorption of glabridin, an active flavonoid from the root of Glycyrrhiza glabra. DMD 2007; 35:539-553.

53. Choi CH, Kang G, Min YD. Reversal of P-glycoprotein-mediated multidrug resistance by protopanaxatriol ginsenosides from Korean red ginseng. Planta Med 2003; 69:235-240.

54. Gao N, Zhang Y, Mao JQ, Li GQ, Zhou W, Gao B et al. Effects of some traditional Chinese drugs on Mdr1 gene and its expression product in K562/A02 cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2008; 16:785-789.

55. Fong WF, Wang C, Zhu GY, Leung CH, Yang MS, Cheung HY. Reversal of multidrug resistance in cancer cells by Rhizoma Alismatis extract. Phytomedicine 2007; 14: 160-165.

56. Geng J, Zhou D. Coriaria lactone induces in vitro the overexpression of multidrug resistance P-glycoprotein in astrocyte from rat brain. Sichuan Da Xue Xue Bao Yi Xue Ban 2008; 39:80-83.

57. Suzuki H, Tanabe H, Mizukami H, Inoue M. Selective regulation of multidrug resistance protein in vascular smooth muscle cells by the isoquinoline alkaloid coptisine. Biol Pharm Bull 2010; 33: 677-682.

58. Qiu W, Jiang XH, Liu CX, Ju Y, Jin JX. Effect of berberine on the pharmacokinetics of substrates of CYP3A and P-gp. Phytotherapy Research 2009; 23: 1553-1558.

59. Vaidyanathan JB, Walle T. Cellular uptake and efflux of the tea flavonoid (-)epicatechin-3-gallate in the human intestinal cell line Caco-2. J Pharmacol Exp Ther 2003; 307: 745-752.

60. Mei Y, Qian F, Wei D, Liu J. Reversal of cancer multidrug resistance by green tea polyphenols. J Pharm Pharmacol 2004; 56:1307-1314.

61. Huang Y, Dong G, Hong X, Chai H, Yuan X. Studies on reversing MDR of K562/A02 by ramification of curcumin hydrolyzed. Zhongguo Zhong Yao Za Zhi 2010; 35: 2460-2463.

62. Ampasavate C, Sotanaphun U, Phattanawasin P, Piyapolrungroj N. Effects of Curcuma spp. on P-glycoprotein function. Phytomedicine 2010; 17:506-512.

63. Hu YJ, Shen XL, Lu HL, Zhang YH, Huang XA, Fu LC et al. Tenacigenin B derivatives reverse P-glycoproteinmediated multidrug resistance inHepG2/Dox cells. J Nat Prod 2008; 71:1049-1051.

64. Dong Y, Zhang Y, Yang Q, Li Y, Zhu X. Absorption of extractive Radix Paeoniae Alba in rat everted gut sacs and its interaction with P-glycoprotein. Zhongguo Zhong Yao Za Zhi 2009; 34:884-888.

65. Chan K, Liu ZQ, Jiang ZH, Zhou H, Wong YF, Xu HX et al. The effects of sinomenine on intestinal absorption of paeoniflorin by the everted rat gut sac model. J Ethnopharmacol 2006; 103: 425-432.

66. Wu JY, Fong WF, Zhang JX, Leung CH, Kwong HL, Yang MS et al. Reversal of multidrug resistance in cancer cells by pyranocoumarins isolated from Radix Peucedani. Eur J Pharmacol 2003; 473: 9-17.

67. Chen HY, Wu TS, Su SF, Kuo SC, Chao PD. Marked decrease of cyclosporin absorption caused by phellamurin in rats. Planta Med 2002; 68:138-141.

68. Zhang R, Jie J, Zhou Y, Cao Z, Li W. Long-term effects of Panax ginseng on disposition of fexofenadine in rats in vivo. Am J Chin Med 2009; 37: 657-667.

69. Zhang J, Zhou F, Wu X, Gu Y, Ai H, Zheng Y et al. 20(S)-ginsenoside Rh2 noncompetitively inhibits P-glycoprotein in vitro and in vivo: a case for herb-drug interactions. Drug Metab Dispos 2010; 38: 2179-2187.

70. Wong VK, Chiu P, Chung SS, Chow LM, Zhao YZ, Yang BB et al. Pseudolaric acid B, a novel microtubuledestabilizing agent that circumvents multidrug resistance phenotype and exhibits antitumor activity in vivo. Clin Cancer Res 2005; 11:6002-6011.

71. Shen H, Xu W, Chen Q, Wu Z, Tang H, Wang F. Tetrandrine prevents acquired drug resistance of K562 cells through inhibition of mdr1 gene transcription. J Cancer Research Clin Oncol 2010; 136: 659-665.

72. Chen YW, Lin GJ, Chuang YP, Chia WT, Hueng DY, Lin CK et al. Triptolide circumvents drug-resistant effect and enhances 5-fluorouracil antitumor effect on KB cells. Anticancer Drugs 2010; 21: 502-513.

Herba Polonica

From Botanical to Medical Research

Journal Information


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 196 196 17
PDF Downloads 89 89 11