Hepatic and renal Bcrp transporter expression in mice treated with perfluorooctanoic acid.
Hepatic and renal Bcrp transporter expression in mice treated with perfluorooctanoic acid.
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DOI：
10.1016/j.tox.2013.02.009
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发表时间：
2013-04-05
期刊：
影响因子：
4.5
通讯作者：
Aleksunes, Lauren M.
中科院分区：
文献类型：
--
作者：
Eldasher, Lobna M.;Wen, Xia;Little, Michael S.;Bircsak, Kristin M.;Yacovino, Lindsay L.;Aleksunes, Lauren M.
乳腺癌耐药蛋白（Bcrp）是一种外排转运蛋白，参与药物和环境化学物质的胆汁和肾脏排泄。最近的证据表明，药物激活过氧化物酶体增殖物激活受体α（PPARα）可以上调肝脏Bcrp的表达。本研究探讨了经PPARα激动剂全氟辛酸（PFOA）处理的小鼠肝脏和肾脏Bcrp mRNA和蛋白的调节以及PFOA在体外改变人BCRP功能的能力。在用溶剂或全氟辛酸（1或3毫克/千克/天口服管饲法）处理7天的雄性C57 BL/6小鼠的肝脏和肾脏中定量Bcrp mRNA和蛋白质表达。PFOA处理增加了肝脏重量以及肝脏PPARα靶基因细胞色素P450 4a 14的mRNA和蛋白表达。与溶剂处理的对照小鼠相比，PFOA使肝脏Bcrp mRNA和蛋白质增加1.5至3倍。免疫荧光染色证实，增强小管Bcrp染色的肝脏切片从全氟辛酸处理的小鼠。在PFOA处理的小鼠中，肾脏细胞色素P450 4a 14 mRNA的表达增加，但Bcrp没有增加。微摩尔浓度的PFOA降低人BCRP ATP酶活性，抑制BCRP介导的倒置膜囊泡转运。总之，这些研究表明，PFOA诱导小鼠肝脏Bcrp表达，并可能在超过人类观察到的浓度水平下抑制人类BCRP转运蛋白功能。
The breast cancer resistance protein (Bcrp) is an efflux transporter that participates in the biliary and renal excretion of drugs and environmental chemicals. Recent evidence suggests that pharmacological activation of the peroxisome proliferator activated receptor alpha (PPARα) can up-regulate the hepatic expression of Bcrp. The current study investigated the regulation of hepatic and renal Bcrp mRNA and protein in mice treated with the PPARα agonist perfluorooctanoic acid (PFOA) and the ability of PFOA to alter human BCRP function in vitro. Bcrp mRNA and protein expression were quantified in the livers and kidneys of male C57BL/6 mice treated with vehicle or PFOA (1 or 3 mg/kg/day oral gavage) for 7 days. PFOA treatment increased liver weights as well as the hepatic mRNA and protein expression of the PPARα target gene, cytochrome P450 4a14. Compared to vehicle-treated control mice, PFOA increased hepatic Bcrp mRNA and protein between 1.5- and 3-fold. Immunofluorescent staining confirmed enhanced canalicular Bcrp staining in liver sections from PFOA-treated mice. The kidney expression of cytochrome P450 4a14 mRNA, but not Bcrp, was increased in mice treated with PFOA. Micromolar concentrations of PFOA decreased human BCRP ATPase activity and inhibited BCRP-mediated transport in inverted membrane vesicles. Together, these studies demonstrate that PFOA induces hepatic Bcrp expression in mice and may inhibit human BCRP transporter function at concentrations that exceed levels observed in humans.
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