Abstract
Aim:
To investigate the modulatory effect of CJZ3, a lomerizine derivative, on P-glycoprotein (P-gp) function in rat brain microvessel endothelial cells (RBMEC).
Methods:
RBMEC were isolated and cultured in Dulbecco's modified Eagle's medium/F12 (1:1)medium, and the amount of intracellular rhodamine 123 (Rh123) was determined using a fluorescence spectrophotometer to evaluate the modulatory effect of CJZ3 on P-gp function.
Results:
The accumulation of Rh123 was potentiated in a concentration-dependent manner after incubation with CJZ3 for RBMEC, but not for human umbilical vein endothelial cells (HUVEC). CJZ3 caused the accumulation of intracellular Rh123 in a time-dependent manner and significantly decreased the efflux of Rh123 from the cells. The inhibitory effect of CJZ3 on P-gp function was reversible and remained for 120 min after CJZ3 (2.5 umol/L) was removed from the medium.
Conclusion:
CJZ3 has a potent in vitro effect on the inhibition of P-gp function.
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References
Germann UA . P-glycoprotein: a mediator of multidrug resistance in tumour cells. Eur J Cancer 1996; 32A: 927–44.
Gottesman MM, Pastan I . Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 1993; 62: 385–427.
Childs S, Ling V . The MDR superfamily of genes and its biological implications. In: DeVita VT, Hellman S, Rosenberg SA Important advances in oncology 1994. Philadelphia: J B Lippin-cott Company. 1994. p 21–36.
Elsinga PH, Hendrikse NH, Bart J, Vaalburg W, Van Waarde A . PET Studies on P-glycoprotein function in the blood-brain barrier: how it affects uptake and binding of drugs within the CNS. Curr Pharm Des 2004; 10: 1493–503.
Cisternino S, Rousselle C, Debray M, Scherrmann JM . In vivo saturation of the transport of vinblastine and colchicine by P-glycoprotein at the rat blood-brain barrier. Pharm Res 2003; 20: 1607–11.
Zhao YL, Du J, Kanazawa H, Sugawara A, Takagi K, Kitaichi K, et al. Effect of endotoxin on doxorubicin transport across blood-brain barrier and P-glycoprotein function in mice. Eur J Pharmacol 2002; 445: 115–23.
Sakata A, Tamai I, Kawazu K, Deguchi Y, Ohnishi T, Saheki A, et al. In vivo evidence for ATP-dependent and P-glycoprotein-mediated transport of cyclosporin A at the blood-brain barrier. Biochem Pharmacol 1994; 48: 1989–92.
Twentyman PR . Modification of cytotoxic drug resistance by non-immuno-suppressive cyclosporins. Br J Cancer 1988; 57: 254–8.
Aszalos A, Thompson K, Yin JJ, Ross DD . Combinations of P-glycoprotein blockers, verapamil, PSC833, and cremophor act differently on the multidrug resistance associated protein (MRP) and on P-glycoprotein (Pgp). Anticancer Res 1999; 19: 1053–64.
Shiraki N, Hamada A, Ohmura T, Tokunaga J, Oyama N, Nakano M . Increase in doxorubicin cytotoxicity by inhibition of P-glycoprotein activity with lomerizine. Biol Pharm Bull 2001; 24: 555–7.
Abbott NJ, Hughes CC, Revest PA, Greenwood J . Development and characterisation of a rat brain capillary endothelial culture: towards an in vitro blood-brain barrier. J Cell Sci 1992; 103: 23–37.
Fontaine M, Elmquist WF, Miller DW . Use of rhodamine 123 to examine the functional activity of P-glycoprotein in primary cultured brain microvessel endothelial cell monolayers. Life Sci 1996; 59: 1521–31.
Sarver JG, Klis WA, Byers JP, Erhardt PW Microplate screening of the differential effects of test agents on Hoechst 33342, rhodamine 123, and rhodamine 6G accumulation in breast cancer cells that overexpress P-glycoprotein. J Biomol Screen 2002; 7: 29–34.
Zhu HJ, Liu GQ . Effect of E6, a novel calmodulin inhibitor, on activity of P-glycoprotein in purified primary cultured rat brain microvessel endothelial cells. Acta Pharmacol Sin 2003; 24: 1143–9.
He L, Liu GQ . Effects of various principles from Chinese herbal medicine on rhodamine123 accumulation in brain capillary endothelial cells. Acta Pharmacol Sin 2002; 23: 591–6.
Green LJ, Marder P, Slapak CA . Modulation by LY335979 of P-glycoprotein function in multidrug-resistant cell lines and human natural killer cells. Biochem Pharmacol 2001; 61: 1393–9.
Ji BS, He L, Liu GQ . Modulation of P-glycoprotein function by amlodipine derivatives in brain microvessel endothelial cells of rats. Acta Pharmacol Sin 2005; 26: 166–70.
Martin C, Berridge G, Higgins CF, Callaghan R . The multi-drug resistance reversal agent SR33557 and modulation of vinca alkaloid binding to P-glycoprotein by an allosteric interaction. Br J Pharmacol 1997; 122: 765–71.
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Project supported by the High Technology Research and Development Program of China (No 2002AA2Z343E) and the Natural Science Foundation of Jiangsu Province, China (No BK 2004110).
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Ji, Bs., He, L., Li, Xq. et al. CJZ3, a lomerizine derivative, modulates P-glycoprotein function in rat brain microvessel endothelial cells. Acta Pharmacol Sin 27, 414–418 (2006). https://doi.org/10.1111/j.1745-7254.2006.00294.x
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DOI: https://doi.org/10.1111/j.1745-7254.2006.00294.x