Thalidomide increases human hepatic cytochrome P450 3A enzymes by direct activation of the pregnane X receptor.
Thalidomide increases human hepatic cytochrome P450 3A enzymes by direct activation of the pregnane X receptor.
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DOI：
10.1021/tx4004374
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发表时间：
2014-02-17
影响因子：
4.1
通讯作者：
Yamazaki H
中科院分区：
文献类型：
--
作者：
Murayama N;van Beuningen R;Suemizu H;Guillouzo CG;Shibata N;Yajima K;Utoh M;Shimizu M;Chesné C;Nakamura M;Guengerich FP;Houtman R;Yamazaki H
最近H. Yamazaki等人（2013）在各种体外和体内模型中使用模型底物咪达唑仑。具有人源化肝脏的嵌合小鼠在口服沙利度胺预处理后也显示出增强的咪达唑仑清除，推测是由于人P450 3A诱导。在本研究中，我们进一步研究了人类肝脏药物代谢酶的调节。沙利度胺增强人肝细胞中P450 3A 4和2B 6 mRNA水平、蛋白表达和/或氧化活性，间接表明参与解毒的上游转录因子的激活，例如核受体雄烷X受体（PXR）和组成型雄烷受体（CAR）。配体结合后的一个关键事件是核受体构象的改变和共调节蛋白的募集，从而改变靶基因的染色质可及性。为了研究沙利度胺对PXR和CAR的直接参与和功能改变，我们利用了具有154个共调节器衍生的核受体相互作用基序和共调节器和核受体盒的肽微阵列，其作为核受体构象和活性状态的传感器作为配体的函数。沙利度胺及其人近代谢物5-羟基沙利度胺显示出与PXR和CAR配体结合结构域的共调节剂相互作用的显著调节，类似于这些受体的已建立的激动剂。这些结果共同表明，沙利度胺作为PXR和CAR的配体，并引起酶诱导，导致P450酶活性增加。沙利度胺治疗人类期间药物相互作用的可能性需要进一步评估。
Heterotropic cooperativity of human cytochrome P450 (P450) 3A4/3A5 by the teratogen thalidomide was recently demonstrated by H. Yamazaki et al. (2013) using the model substrate midazolam in various in vitro and in vivo models. Chimeric mice with humanized liver also displayed enhanced midazolam clearance upon pre treatment with orally administered thalidomide, presumably because of human P450 3A induction. In the current study, we further investigated the regulation of human hepatic drug metabolizing enzymes. Thalidomide enhanced levels of P450 3A4 and 2B6 mRNA, protein expression, and/or oxidation activity in human hepatocytes, indirectly suggesting activation of upstream transcription factors involved in detoxication, e.g. the nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). A key event after ligand binding is an alteration of nuclear receptor conformation and recruitment of co regulator proteins that alter chromatin accessibility of target genes. To investigate direct engagement and functional alteration of PXR and CAR by thalidomide, we utilized a peptide microarray with 154 co regulator derived nuclear receptor interaction motifs and co regulator and nuclear receptor boxes, which serves as a sensor for nuclear receptor conformation and activity status as a function of ligand. Thalidomide and its human proximate metabolite 5 hydroxythalidomide displayed significant modulation of co regulator interaction with PXR and CAR ligand binding domains, similar to established agonists for these receptors. These results collectively suggest that thalidomide acts as a ligand for PXR and CAR and causes enzyme induction leading to increased P450 enzyme activity. The possibilities of drug interactions during thalidomide therapy in humans require further evaluation.
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影响因子：
2.7
作者：
Yamamoto, Takeshi;Shibata, Norio;Sasaki, Takuma
通讯作者：
Sasaki, Takuma
影响因子：
4.1
作者：
Chowdhury, Goutam;Murayama, Norie;Yamazaki, Hiroshi
通讯作者：
Yamazaki, Hiroshi
影响因子：
56.9
作者：
Ito, Takumi;Ando, Hideki;Handa, Hiroshi
通讯作者：
Handa, Hiroshi
影响因子：
4.1
作者：
Yamazaki H;Suemizu H;Murayama N;Utoh M;Shibata N;Nakamura M;Guengerich FP
通讯作者：
Guengerich FP
影响因子：
4.1
作者：
Yamazaki H;Suemizu H;Shimizu M;Igaya S;Shibata N;Nakamura M;Chowdhury G;Guengerich FP
通讯作者：
Guengerich FP