BÜNYAMİN TRAŞ, Gül ÇETİN, KAMİL ÜNEY, Burak DIK, ORHAN ÇORUM, Sema ATALAY

Aflatoksin B1'in Fare Beynine Geçişi Üzerine BCRP ve P-gp Modülatörlerinin Etkisi

Çalışma, zosuquidar ve prazosin tarafından sırasıyla P-gp ve BCRP modülasyonunun AFB1'in plazma ve beyin konsantrasyonlarının etkileyip etkilemediğini belirlemek için gerçekleştirildi. Bu çalışmada, 40 adet sağlıklı, erkek BALB/c ırkı fare (32±3.7 g) kullanıldı. Hayvanlar her grupta 8 fare olacak şekilde rastgele 5 gruba ayrıldı. Grup 1, metod validasyon çalışmalarında kullanıldı. Grup 2 (AF)'ye AFB1 20 mg/kg dozda intraperitoneal yolla verildi. Grup 3 (AF+PRZ), 4 (AF+ZQR) ve 5 (AF+PRZ+ZQR)'e ise sırasıyla intraperitoneal yolla prazosin (0.3 mg/kg), zosuquidar (25 mg/kg) ve prazosin+zosuquidar (0.3 mg/kg prazosin + 25 mg/kg zosuquidar) uygulamalarından 30 dk. sonra AFB1 20 mg/kg dozda intraperitoneal yolla uygulandı. Grup 2-5'de bulunan hayvanlardan AFB1 uygulamasından sonraki 6. saatte kan ve beyin örnekleri alındı. AFB1 düzeyleri fluoresans dedektör içeren HPLC sisteminde tayin edildi. Prazosin ve zosuquidarın tek ve eşzamanlı uygulanması AFB1'in beyin konsantrasyonlarında sadece AFB1uygulamasına göre önemli oranda azalmaya neden oldu (P

Effects of BCRP and P-gp Modulators on the Penetration of Aflatoxin B1 into the Mouse Brain

This study was conducted to determine whether the plasma and brain concentrations of AFB1 are affected by the modulation of P-gp and BCRP using zosuquidar (ZQR) and prazosin (PRZ), respectively. In this study, a total of 40 healthy adult male BALB/c mice (32±3.7 g) were used. The animals were randomly divided into 5 groups, with 8 animals per group. Group 1 was used for method validation. Group 2 (AF) received intraperitoneal AFB1at a dose of 20 mg/kg of body weight. Groups 3 (AF+PRZ), 4 (AF+ZQR), and 5 (AF+PRZ+ZQR) received 20 mg/kg of AFB1 intraperitoneally 30 min after the intraperitoneal administration of prazosin (0.3 mg/kg), zosuquidar (25 mg/kg), and prazosin+zosuquidar (0.3 mg/kg prazosin + 25 mg/kg zosuquidar), respectively. Six hours after the administration of AFB1, blood and brain samples were collected from the animals in Groups 2 to 5. AFB1concentrations were determined using an HPLC system with fluorescence detection. Individual and simultaneous administration of prazosin and zosuquidar significantly reduced the brain concentrations of AFB1 in comparison to a single administration of AFB1 (P<0.05). The brain/plasma ratio of the AF group was higher than that of the other groups (AF+PRZ, AF+ZQR, and AF+PRZ+ZQR) (P<0.05). Inducers of transmembrane proteins, especially BCRP, can be life saving during acute AFB1 poisoning.

PDF

___

1. Dalvi RR: An overview of aflatoxicosis of poultry its characteristics, prevention and reduction. Vet Res Commun, 10, 429-443, 1986. DOI: 10.1007/BF02214006
2. Oguz H: A review from experimental trials on detoxification of aflatoxin in poultry feed. Eurasian J Vet Sci, 27, 1-12, 2011.
3. Zain ME: Impact of mycotoxins on humans and animals. J Saudi Chem Soc, 15, 129-144, 2011. DOI: 10.1016/j.jscs.2010.06.006
4. Bortell R, Asquith RL, Edds GT, Simpson GF: Acute experimentally induced aflatoxicosis in the weanling pony. Am J Vet Res, 44, 2110-2114, 1983.
5. Chao TC, Maxwell SM, Wong SY: An outbreak of aflatoxicosis and boric acid poisoning in Malaysia: A clinicopathological study. J Pathol, 164, 225-233, 1991. DOI: 10.1002/path.1711640307
6. Bastaki SA, Osman N, Kochiyil J, Shafiullah M, Padmanabhan R, Abdulrazzaq YM: Toxicokinetics of aflatoxin in pregnant mice. Int J Toxicol, 29, 425-431, 2010. DOI: 10.1177/1091581810369565
7. Bailey DG: Fruit juice inhibition of uptake transport: A new type of food-drug interaction. Brit J Clin Pharmacol, 70, 645-655, 2010. DOI: 10.1111/j.1365-2125.2010.03722.x
8. Abdallah HM, Al-Abd AM, El-Dine RS, El-Halawany AM: P-glycoprotein inhibitors of natural origin as potential tumor chemosensitizers: A review. J Adv Res, 6, 45-62, 2015. DOI: 10.1016/j.jare.2014.11.008
9. An G, Mukker JK, Derendorf H, Frye RF: Enzyme- and transportermediated beverage-drug interactions: An update on fruit juices and green tea. J Clin Pharmacol, 55, 1313-1331, 2015. DOI: 10.1002/jcph.563
10. Van Herwaarden AE, Wagenaar E, Karnekamp B, Merino G, Jonker JW, Schinkel AH: Breast cancer resistance protein (Bcrp1/Abcg2) reduces systemic exposure of the dietary carcinogens aflatoxin B1, IQ and Trp-P-1 but also mediates their secretion into breast milk. Carcinogenesis, 27, 123- 130, 2006. DOI: 10.1093/carcin/bgi176
11. Robey RW, To KKK, Polgar O, Dohse M, Fetsch P, Dean M, Bates SE: ABCG: A perspective. Adv Drug Deliver Rev, 61, 3-13, 2009. DOI: 10.1016/j. addr.2008.11.003
12. Loe DW, Stewart RK, Massey TE, Deeley RG, Cole SP: ATP-dependent transport of aflatoxin B1 and its glutathione conjugates by the product of the multidrug resistance protein (MRP) gene. Mol Pharmacol, 51, 1034-1041, 1997.
13. Löscher W, Potscka H: Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol, 76, 22-76, 2005. DOI: 10.1016/j.pneurobio.2005.04.006
14. Sharom FJ: 2008: ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics, 9, 105-127, 2008. DOI: 10.2217/14622416.9.1.105
15. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM: International transporter consortium. Membrane transporters in drug development. Nat Rev Drug Discov, 9, 215-236, 2010. DOI: 10.1038/nrd3028
16. Eisenblatter T, Galla HJ: A new multidrug resistance protein at the blood-brain barrier. Biochem Biophys Res Commun, 293, 1273-1278, 2002. DOI: 10.1016/S0006-291X(02)00376-5
17. Aszalos A: Role of ATP-binding cassette (ABC) transporters in interactions between natural products and drugs. Curr Drug Metab, 9, 1010-1018, 2008. DOI: 10.2174/138920008786927776
18. Zhou SF: Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica, 38, 802-832, 2008. DOI: 10.1080/00498250701867889
19. Durmus S, Xu N, Sparidans IRW, Wagenaar E, Beijnenb JH, Schinkel AH: P-glycoprotein (MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) restrict brain accumulation of the JAK1/2 inhibitor, CYT387. Pharmacol Res, 76, 9-16, 2013. DOI: 10.1016/j.phrs.2013.06.009
20. AOAC (Association of Official Analytical Chemist): Official method of analysis. Natural Toxins. Vol. 2, 17th edn., 20-22, Association of Official Analytical Chemist, Gaithersburg, MD, USA, 2000.
21. Chiavaro E, Cacchioli C, Berni E, Spotti E: Immunoaffinity cleanup and direct fluorescence measurement of aflatoxins B1 and M1 in pig liver: Comparison with high-performance liquid chromatography determination. Food Addit Contam, 22, 1154-1161, 2005. DOI: 10.1080/ 02652030500307115
22. Hooper DG, Bolton VE, Guilford FT, Straus DC: Mycotoxin detection in human samples from patients exposed to environmental molds. Int J Mol Sci, 10, 1465-1475, 2009. DOI: 10.3390/ijms10041465
23. Gangolli S: The dictionary of substances and their effects. In, Gangolli S (Ed): The Royal Society of Chemistry. 2nd edn., Cambridge, England, 1999.
24. Takano M, Yumoto R, Murakami T: Expression and function of efflux drug transporters in the intestine. Pharmacol Ther, 109, 137-161, 2006. DOI: 10.1016/j.pharmthera.2005.06.005
25. Liu Y, Liu H, Yang H, Wen T, Shang Y, Liu X, Xie L, Wang G: Impaired expression and function of breast cancer resistance protein (Bcrp) in brain cortex of streptozocin-induced diabetic rats. Biochem Pharmacol, 74, 1766-1772, 2007. DOI: 10.1016/j.bcp.2007.08.021
26. Juvale K. Wiese M: 4-Substituted-2-phenylquinazolines as inhibitors of BCRP. Bioorg Med Chem Lett, 22, 6766-6769, 2012. DOI: 10.1016/j. bmcl.2012.08.024
27. Takara K, Yamamoto K, Matsubara M, Minegaki T, Takahashi M, Yokoyama T, Okumura K: Effects of ?-adrenoceptor antagonists on ABCG2/BCRP-mediated resistance and transport. PLoS One 7 (2): e30697. 2012. DOI: 10.1371/journal.pone.0030697
28. Tanaka Y, Slitt AL, Leazer TM, Maher JM, Klaassen CD: Tissue distribution and hormonal regulation of the breast cancer resistance protein (Bcrp/Abcg2) in rats and mice. Biochem Biophys Res Commun, 326, 181-187, 2004. DOI: 10.1016/j.bbrc.2004.11.012
29. González-Lobato L, Real R, Prieto JG, Alvarez AI, Merino G: Differential inhibition of murine Bcrp1/Abcg2 and human BCRP/ABCG2 by the mycotoxin fumitremorgin C. Eur J Pharmacol, 644, 41-48, 2010. DOI: 10.1016/j.ejphar.2010.07.016
30. Zong J, Pollack GM: Modulation of P-glycoprotein transport activity in the mouse blood-brain barrier by rifampin. J Pharmacol Exp Ther, 306, 556-562, 2003. DOI: 10.1124/jpet.103.049452
31. Cetin G, Tras B, Uney K: Effects of dexamethasone and fexofenadine on the penetration into brain and testes tissues of levofloxacin, a P-gp substrate. 12th International Congress of the European Association for Veterinary Pharmacology and Toxicology (EAVPT 2012), July 8-12, Noordwijkerhout-Netherlands, 2012.
32. Enokizono J, Kusuhara H, Ose A, Schinkel AH, Sugiyama Y: Quantitative investigation of the role of breast cancer resistance protein (Bcrp/Abcg2) in limiting brain and testis penetration of xenobiotic compounds. Drug Metab Dispos, 36, 995-1002, 2008. DOI: 10.1124/ dmd.107.019257
33. Zhou L, Schmidt K, Nelson FR, Zelesky V, Troutman MD: The effect of breast cancer resistance protein and P-glycoprotein on the brain penetration of flavopiridol, imatinib mesylate (Gleevec), prazosin, and 2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl) propanoic acid (PF-407288) in mice. Drug Metab Dispos, 37, 946-955, 2009. DOI: 10.1124/dmd.108.024489
34. Cripe LD, Uno H, Paietta EM, Litzow MR, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Luger S, Tallman MS: Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: A randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999. Blood, 116, 4077-4085, 2010. DOI: 10.1182/blood-2010-04-277269
35. Mittapalli RK, Vaidhyanathan S, Sane R, Elmquıst WF: Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: Vemurafenib (PLX4032). J Pharmacol Exp Ther, 342, 33-40, 2012. DOI: 10.1124/jpet.112.192195
36. De Lange EC, Marchand S, van den Berg D, van der Sandt IC, de Boer AG, Delon A, Bouquet S, Couet W: In vitro and in vivo investigations of fluoroquinolones: Effects of the P-glycoprotein efflux transporter on brain distribution of sparfloxacin. Eur J Pharm Sci, 12, 85-93, 2000. DOI: 10.1016/S0928-0987(00)00149-4
37. Tamai, I, Yamashita J, Kido Y, Ohnari A, Sai Y, Shıma Y, Naruhashi K, Koizumi S, Tsuji A: Limited distribition of new quinolone antibacterial agents into brain caused by multiple efflux transporters at the bloodbrain barrier. J Pharmacol Exp Ther, 295, 146-152, 2000.
38. Demeule M, Jodoin J, Beaulieu E, Brossard M, Beliveau R: Dexamethasone modulation of multidrug transporters in normal tissues. Febs Letters, 442, 208-214, 1999. DOI: 10.1016/S0014-5793(98)01663-9
39. Drescher S, Glaeser H, Mürdter T, Hitzl M, Eichelbaum M, Fromm MF: P-glycoprotein-mediated intestinal and biliary digoxin transport in humans. Clin Pharmacol Ther, 73, 223-231, 2003. DOI: 10.1067/mcp. 2003.27
40. Kirby GM, Chemin I, Montesano R, Chisari FV, Lang MA, Wild VP: Induction of specific cytochrome P450s involved in aflatoxin B1 metabolism in hepatitis B virus transgenic mice. Mol Carcinogen, 11, 74- 80, 1994. DOI: 10.1002/mc.2940110204
41. Van Vleet TR, Klein PJ, Coulombe RA: Metabolism of aflatoxin B1 by normal human bronchial epithelial cells. J Toxicol Environ Health Part A, 63, 525-540, 2001. DOI: 10.1080/15287390152410156
42. Yang X, Lu H, Li Z, Bian Q, Qiu L, Li Z, Liu Q, Li J, Wang X, Wang S: Cytochrome P450 2A13 mediates aflatoxin B1-induced cytotoxicity and apoptosis in human bronchial epithelial cells. Toxicology, 300, 138-148, 2012. DOI: 10.1016/j.tox.2012.06.010