Regulation of mouse organic anion-transporting polypeptides (Oatps) in liver by prototypical microsomal enzyme inducers that activate distinct transcription factor pathways
Regulation of mouse organic anion-transporting polypeptides (Oatps) in liver by prototypical microsomal enzyme inducers that activate distinct transcription factor pathways
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DOI：
10.1124/dmd.105.003988
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发表时间：
2005-09-01
影响因子：
3.9
通讯作者：
Klaassen, CD
中科院分区：
文献类型：
--
作者：
Cheng, XG;Maher, J;Klaassen, CD
药物代谢酶和转运蛋白是影响外源性物质在体内处置的关键因素。微粒体酶诱导剂类的I相酶诱导通过激活转录因子如芳香烃受体（AhR）、组成型雄烷受体（CAR）、雄烷X受体（PXR）、过氧化物酶体增殖物激活受体α（PPAR α）和核因子红细胞2相关因子2（Nrf 2）而发生。然而，这些因素对有机阴离子转运多肽（Oatp）摄取转运蛋白的调控知之甚少。肝脏Oatp摄取的一些化学物质必须发生之前的生物转化，因此，我们假设，表达的Oatps和生物转化酶协调调节肝脏。在本研究中，已知的AhR，CAR，PXR，PPAR α和Nrf 2的化学活化剂对小鼠Oatps和药物代谢酶的肝脏mRNA表达的影响通过分支DNA测定进行定量。所有化学品都增加了其充分表征的靶药物代谢酶的表达：AhR配体增加Cyp 1A 1，CAR激活剂增加Cyp 2B 10，PXR配体增加Cyp 3A 11，PPAR α配体增加Cyp 4A 14，Nrf 2激活剂诱导NAD（P）H：醌氧化还原酶1。AhR配体（2，3，7，8-四氯二苯并-p-二恶英、多氯联苯126和β-萘啶酮）增加肝脏中Oatp 2b 1和3a 1 mRNA的表达。CAR激活剂[苯巴比妥、1，4-双[2-（3，5-二氯吡啶氧基）]苯和二烯丙基硫醚]降低Oatp 1a 1 mRNA表达。两种PXR配体[双烯醇酮-16 α-甲腈（PCN）和螺内酯]增加肝脏中Oatp 1a 4 mRNA的表达，而PXR配体（PCN，螺内酯和地塞米松）和PPAR α配体（氯贝特，环丙贝特和邻苯二甲酸二乙基己酯）降低肝脏中Oatp 1a 1，1b 2，2a 1和2b 1 mRNA的表达。Nrf 2激活剂（oltipraz，ethoxquin和butylated hydroxyanisole）下调Oatp 1a 1，但上调Oatp 2b 1 mRNA的表达。因此，只有少数转录因子激活剂增加了Oatp表达，令人惊讶的是，许多转录因子激活剂降低了Oatp表达。
Drug-metabolizing enzymes and transporters are key factors that affect disposition of xenobiotics. Phase I enzyme induction by classes of microsomal enzyme inducers occurs via activation of transcription factors such as aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor alpha (PPAR alpha), and nuclear factor erythroid 2-related factor 2 (Nrf2). However, regulation of organic anion-transporting polypeptide (Oatp) uptake transporters by these factors is poorly understood. Hepatic Oatp uptake of some chemicals must occur prior to biotransformation; thus, we hypothesize that expression of Oatps and biotransformation enzymes is coordinately regulated in liver. In the present study, the effects of known chemical activators of AhR, CAR, PXR, PPAR alpha, and Nrf2 on the hepatic mRNA expression of mouse Oatps and drug-metabolizing enzymes were quantified by the branched DNA assay. All chemicals increased the expression of their well characterized target drug-metabolizing enzymes: AhR ligands increased Cyp1A1, CAR activators increased Cyp2B10, PXR ligands increased Cyp3A11, PPAR alpha ligands increased Cyp4A14, and Nrf2 activators induced NAD(P)H:quinone oxidoreductase 1. AhR ligands (2,3,7,8-tetrachlorodibenzo-p-dioxin, polychlorinated biphenyl 126, and beta-naphthoflavone) increased Oatp2b1 and 3a1 mRNA expression in liver. CAR activators [phenobarbital, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, and diallyl sulfide] decreased Oatp1a1 mRNA expression. Two PXR ligands [pregnenolone-16 alpha-carbonitrile (PCN) and spironolactone] increased Oatp1a4 mRNA expression in liver, whereas PXR ligands (PCN, spironolactone, and dexamethasone) and PPAR alpha ligands (clofibrate, ciprofibrate, and diethylhexylphthalate) decreased Oatp1a1, 1b2, 2a1, and 2b1 mRNA expression in liver. Nrf2 activators (oltipraz, ethoxyquin, and butylated hydroxyanisole) down-regulated Oatp1a1 but up-regulated Oatp2b1 mRNA expression. Therefore, only a few transcription factor activators increased Oatp expression, and, surprisingly, many decreased Oatp expression.