Induction of the multidrug resistance-associated protein family of transporters by chemical activators of receptor-mediated pathways in mouse liver
Induction of the multidrug resistance-associated protein family of transporters by chemical activators of receptor-mediated pathways in mouse liver
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DOI：
10.1124/dmd.105.003798
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发表时间：
2005-07-01
影响因子：
3.9
通讯作者：
Klaassen, CD
中科院分区：
文献类型：
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作者：
Maher, JM;Cheng, XG;Klaassen, CD
多药耐药相关蛋白（multidrug resistance-associated proteins，Mrp）是一种ATP依赖性转运蛋白，可将多种结合和非结合的化合物转运到细胞外。在人类中有9种已鉴定的Mrp转运蛋白，除Mrp 8外，所有转运蛋白均与鼠同源。由于核受体介导I相酶的诱导，因此Mrp转运蛋白的表达可能受到这些受体的类似调节，以协调肝脏化学物质的代谢和输出。为了检验Mrp表达可能与肝脏中I相酶表达协同调节的假设，给出了代表已知转录介导途径的15种不同化合物：芳烃受体（AhR）、甾烷X受体（PXR）、组成型雄烷受体（CAR）、过氧化物酶体增殖物激活受体α（PPAR α）和核因子-E2相关因子2（Nrf 2）。这些化合物中的每一种都诱导其各自的靶酶在肝脏中的表达，表明化学方案是有效的。AhR配体[2，3，7，8-四氯二苯并-对-二恶英（TCDD）、多氯联苯126（PCB 126）和β-萘酮]诱导Mrp 2、-3、-5和-6 mRNA表达。CAR激活剂1，4-双[2-（3，5-二氯吡啶氧基）]苯（TCPOBOP）诱导Mrp 2、-3、-4、-6和-7 mRNA表达。Mrp 3也被另外两种CAR激活剂苯巴比妥和二烯丙基硫醚、两种PXR配体、双烯丙酮-16 α-腈和螺内酯以及PPAR配体氯贝特、环丙贝特和邻苯二甲酸二乙基己酯诱导。Nrf 2激活剂（丁基羟基茴香醚、奥替普拉和乙氧喹）诱导Mrp 2 - 6。总之，提出了多种Mrp 3诱导机制，包括AhR、CAR、PXR、PPAR α和Nrf 2，而总体上，观察到AhR和Nrf 2在Mrp家族的肝诱导中的主要作用。因此，这些特异性转录因子参与药物代谢和外排转运的调节。
The multidrug resistance-associated proteins (Mrp) are ATP-dependent transporters that export a variety of conjugated and unconjugated compounds out of cells. There are nine identified Mrp transporters in humans, with murine orthologs for all except Mrp8. Because nuclear receptors mediate induction of phase I enzymes, Mrp transporter expression might be similarly regulated by these receptors to coordinate metabolism and export of chemicals from liver. To test the hypothesis that Mrp expression may be coordinately regulated with phase I enzyme expression in liver, 15 different compounds were given representing known transcriptionally mediated pathways: aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor alpha (PPAR alpha), and nuclear factor-E2-related factor 2 (Nrf2). Each of these compounds induced expression of their respective target enzyme in liver, demonstrating that the chemical regimens were effective. The AhR ligands [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated biphenyl 126 (PCB126), and beta-naphthoflavone] induced Mrp2, -3, -5, and -6 mRNA expression. The CAR activator 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) induced Mrp2, -3, -4, -6, and -7 mRNA expression. Mrp3 was also induced by two other CAR activators phenobarbital and diallyl sulfide, two PXR ligands, pregnenalone-16 alpha-carbonitrile and spironolactone, and the PPAR ligands clofibrate, ciprofibrate, and diethylhexylphthalate. The Nrf2 activators (butylated hydroxyanisole, oltipraz, and ethoxyquin) induced Mrp2 -6. In conclusion, a variety of mechanisms are suggested for Mrp3 induction, including AhR, CAR, PXR, PPAR alpha, and Nrf2, whereas on a whole, a predominant role for AhR and Nrf2 in hepatic induction of the Mrp family was observed. Thus, these specific transcription factors are implicated in regulation of both drug metabolism and efflux transport.