There are a number of compounds that can modify the activity of ABC (ATP-binding cassette) and SLC (solute carrier) transporters in the blood-brain barrier (BBB). The aim of this study was to investigate the effect of natural and synthetic substances on the expression level of genes encoding transporters present in the BBB (mdr1a, mdr1b, mrp1, mrp2, oatp1a4, oatp1a5 and oatp1c1). Our results showed that verapamil caused the greatest reduction in the mRNA level while other synthetic (piracetam, phenobarbital) and natural (codeine, cyclosporine A, quercetin) substances showed a selective inhibitory effect. Further, the extract from the roots of Panax ginseng C. A. Meyer exhibited a decrease of transcription against selected transporters whereas the extract from Ginkgo biloba L. leaves resulted in an increase of the expression level of tested genes, except for mrp2. Extract from the aerial parts of Hypericum perforatum L. was the only one to cause an increased mRNA level for mdr1 and oatp1c1. These findings suggest that herbs can play an important role in overcoming the BBB and multidrug resistance to pharmacotherapy of brain cancer and mental disorders, based on the activity of selected drug-metabolizing enzymes and transporters located in the BBB
1. N. J. Abbott, Blood-brain barrier structure and function and the challenges for CNS drug delivery, J. Inherit. Metab. Dis. 36 (2013) 437-449; DOI: 10.1007/s10545-013-9608-0.
2. L. A. Khawli and S. Prabhu, Drug delivery across the blood-brain barrier, Mol. Pharm. 10 (2013) 1471-1472; DOI: 10.1021/mp400170b.
3. A. H. Schinkel, J. J. Smith, O. van Tellingen, J. H. Beijnen, E. Wagenaar, L. van Deemter, C. A. Mol, M. A. van der Valk, E. C. Robanus-Maandag and H. P. te Riele, Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs, Cell 77 (1994) 491-502; DOI: 10.1016/0092-8674(94)90212-7.
4. D. S. Miller, Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier, Trends Pharmacol. Sci. 31 (2010) 246-254; DOI: 10.1016/j.tips.2010.03.003.
5. J. Malmo, A. Sandvig, M. K. Varum and S. P. Strand, Nanoparticle mediated P-glikoprotein silencing for improved drug delivery across the blood-brain barrier: a siRNA-chitosan approach, PLoS ONE 8 (2013) e54182; DOI: 10.1371/journal.pone.0054182.
6. F. J. Sharom, ABC multidrug transporters: structure, function and role in chemoresistance, Pharmacogenomics 9 (2008) 105-127; DOI: 10.2217/146224126.96.36.199.
7. C. J. Bachmeier, W. J. Trickler and D. W. Miller, Comparison of drug efflux transport kinetics in various blood-brain barrier models, Drug Metab. Dispos. 34 (2006) 998-1003; DOI: 10.1124/dmd. 105.006999.
8. S. P. C. Cole, Targeting multidrug resistance protein 1 (MRP1, ABCC1): past, present, and future, Annu. Rev. Pharmacol. Toxicol. 54 (2014) 95-117; DOI: 10.1146/annurev-pharmtox-011613-135959.
9. S. A. Kliewer, The nuclear pregnane X receptor regulates xenobiotic detoxification, J. Nutr. 133 (2003) 2444S-2447S.
10. B. I. Sikic, Modulation of multidrug resistance: at the threshold, J. Clin. Oncol. 11 (1993) 1629-1635.
11. T. Eichhorn and T. Efferth, P-glycoprotein and its inhibition in tumors by phytochemicals derived from Chinese herbs, J. Ethnopharmacol. 141 (2012) 557-570; DOI: 10.1016/j.jep.2011.08.053.
12. O. Khantamat, W. Chaiwangyen and P. Limtrakul, Screening of flavonoids for their potential inhibitory effect on p-glycoprotein activity in human cervical carcinoma kb cells, Chiang Mai Med. Bull. 43 (2004) 45-56.
13. S. Zhou, L. Y. Lim and B. Chowbay, Herbal modulation of P-glycoprotein, Drug Metab. Rev. 36 (2004) 57-104.
14. P. Limtrakul, O. Khantamat and K. Pintha, Inhibition of P-glycoprotein function and expression by kaempferol and quercetin, J. Chemother. 17 (2005) 86-95; DOI: 10.1179/joc.2005.17.1.86.
15. European Pharmacopoeia, 6th ed., Vol. 2, Council of Europe, Strassbourg Cedex 2008.
16. T. Sugamo, K. Nakamura and H. Tamura, Effects of cytochrome P450 inducers on the gene expression of ocular xenobiotic metabolizing enzymes in rats, J. Health Sci. 55 (2009) 923-929; DOI: 10.1248/jhs.55.923.
17. U. Andersson, K. Grankvist, A. T. Bergenheim, P. Behnam-Motlagh, H. Hedman and R. Henriksson, Rapid induction of long-lasting drug efflux activity in brain vascular endothelial cells but not malignant glioma following irradiation, Med. Oncol. 19 (2002) 1-9.
18. R. Zhang, J. Jie, Y. Zhou, Z. Cao and W. Li, Long-term effects of Panax ginseng on disposition of fexofenadine in rats in vivo, Am. J. Chin. Med. 37 (2009) 657-667; DOI: 10.1142/S0192415X09007144.
19. J. Zhang, F. Zhou, X. Wu, Y. Gu, H. Ai, Y. Zheng, Y. Li, X. Zhang, G. Hao, J. Sun, Y. Peng and G. Wang, 20(S)-ginsenoside Rh2 noncompetitively inhibits P-glycoprotein in vitro and in vivo: a case for herb-drug interactions, Drug Metab. Dispos. 38 (2010) 2179-2187; DOI: 10.1124/dmd. 110.034793.
20. A. Kawase, A. Yamada, Y. Gamou, Ch. Tahara, F. Takeshita, K. Murata, H. Matsuda, K. Samukawa and M. Iwaki, Effects of ginsenosides on the expression of cytochrome P450s and transporters involved in cholesterol metabolism, J. Nat. Med. (2013); DOI 10.1007/s11418-013-0791-y.
21. M. Hennessy, D. Kelleher, J. P. Spiers, M. Barry, P. Kavanagh, D. Back, F. Mulcahy and J. Feely, St Johns wort increases expression of P-glycoprotein: implications for drug interactions, Br. J. Clin. Pharmacol. 53 (2002) 75-82; DOI: 10.1046/j.0306-5251.2001.01516.x.
22. C. C. Weber, S. Kressmann, G. Fricker and W. E. Muller, Modulation of P-glycoprotein function by St John’s wort extract and its major constituents, Pharmacopsychiatry 37 (2004) 292-298; DOI: 10.1055/s-2004-832686.
23. Ch. Garrovo, A. Rosati, F. Bartoli and G. Decorti, St John’s wort modulation and developmental expression of multidrug transporters in the rat, Phytother. Res. 20 (2006) 468-473; DOI: 10.1002/ ptr.1880.
24. L. Li, J. D. Stanton, A. H. Tolson, Y. Luo and H. Wang, 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. 26 (2009) 872-882; DOI: 10.1007/s11095-008-9788-8.
25. G. Scambia, F. O. Ranelletti, P. B. Panici, R. De Vincenzo, G. Bonanno, G. Ferrandina, M. Piantelli, S. Bussa, C. Rumi, M. Cianfriglia and S. Mancuso, Quercetin potentiates the effect of adriamycin in a multidrug-resistant MCF-7 human breast-cancer cell line: P-glycoprotein as a possible target, Cancer Chemoth. Pharm. 34 (1994) 459-464; DOI: 10.1371/journal.pone.0051764.
26. A. B. Shapiro and V. Ling, Effect of quercetin on Hoechst 33342 transport by purified and reconstituted P-glycoprotein, Biochem. Pharmacol. 53 (1997) 587-596; DOI: 10.1016/S0006-2952(96) 00826-X.
27. M. E. Morris and S. Zhang, Flavonoid-drug interactions: Effects of flavonoids on ABC transporters, Life Sci. 78 (2006) 2116-2130; DOI: 10.1016/j.lfs. 2005.12.003.