科研之友
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摘要
P-glycoprotein is an efflux pump belonging to the ATP-binding cassette superfamily that influences the bioavailability and disposition of many drugs. Mammary epithelial cells express various drug transporters including P-glycoprotein, albeit at low level during lactation. During inflammatory reactions, which can be associated with changes in epithelial barrier functions, pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) are elevated in milk and serum. In this study, the role of TNF-alpha in the regulation of P-glycoprotein was determined in cultured BME-UV cells, an immortalized bovine mammary epithelial cell line. The protein production of P-glycoprotein and mRNA expression of bABCB1, the gene encoding P-glycoprotein, were increased after 24 h of TNF-alpha exposure. The highest observed effects for TNF-alpha on the regulation of P-glycoprotein was after 72 h of exposure. Protein and mRNA expression also increased significantly after 120 h of TNF-alpha exposure, but was lower than the level observed in the cells exposed to TNF-alpha for 72 h. The apical to basolateral flux of digoxin, a P-glycoprotein substrate, was decreased in the TNF-alpha-exposed epithelium. This effect was reversed when verapamil or ketoconazole, compounds known to interact with P-glycoprotein, were added together with digoxin into the donor compartment. Probenecid, a compound known to interact with organic anion transporters, but not P-glycoprotein, did not increase the flux of digoxin. This model has important implications for understanding the barrier function of the mammary epithelium and provides insight into the role of P-glycoprotein in the accumulation and/or removal of xenobiotics from milk and/or plasma.
- 出版日期2010-12
