Kobayashi Kaoru, Yamagami Saeko, Higuchi Tomoaki, Hosokawa Masakiyo, Chiba Kan
Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan.
Drug Metab Dispos. 2004 Apr;32(4):468-72. doi: 10.1124/dmd.32.4.468.
The ligand-binding domain of human pregnane X receptor (hPXR) is highly hydrophobic and flexible, allowing promiscuity in accepting structurally diverse ligands. However, little information is available regarding the critical substituents of compounds involved in the activation of hPXR. The aim of this study was to determine the structure-activity relationships for hPXR-mediated transactivation by barbiturates, hydantoins, and macrolide antibiotics. Most of the barbiturates studied (mephobarbital, pentobarbital, phenobarbital, etc.) activated hPXR. However, barbital, which has a low hydrophobic moiety at the 5-position, and primidone, which has no carbonyl moiety at the 2-position, did not activate hPXR. Therefore, a hydrophobic moiety at the 5-position and a hydrogen-bond acceptor being sufficiently separated from the phenyl-ring are responsible for activation of hPXR by barbiturates. In the case of hydantoins, only mephenytoin and ethotoin, which have an alkylchain at the R1-position, strongly activated hPXR at 300 microM. Phenytoin and 5-(4-methylphenyl)-5-phenylhydantoin, which contain a phenyl or methylphenyl group at both R2- and R3-positions, also activated hPXR, whereas 5-(4-hydroxyphenyl)-5-phenylhydantoin did not activate the receptor. These results suggest that the presence of an alkyl-chain at the R1-position and the presence of bulky and hydrophobic moieties at both R2- and R3-positions are important factors for activation of hPXR by hydantoins. In the case of macrolide antibiotics, troleandomycin, but not oleandomycin, showed significant activation of hPXR. Therefore, triacetate esterification of oleandomycin might increase the hydrophobicity and enhance the activation of hPXR. These findings suggest that hydrophobicity of the ligand and adequate distance between the hydrogen-bond acceptor and the hydrophobic group are important for hPXR activation.
人孕烷X受体（hPXR）的配体结合结构域高度疏水且具有柔性，使得它能够杂乱地接受结构多样的配体。然而，关于参与hPXR激活的化合物的关键取代基，目前可用信息很少。本研究的目的是确定巴比妥类、乙内酰脲类和大环内酯类抗生素介导hPXR反式激活的构效关系。所研究的大多数巴比妥类药物（美索比妥、戊巴比妥、苯巴比妥等）均可激活hPXR。然而，在5位具有低疏水部分的巴比妥以及在2位没有羰基部分的扑米酮，均未激活hPXR。因此，5位的疏水部分以及氢键受体与苯环充分分离是巴比妥类药物激活hPXR的原因。对于乙内酰脲类药物，只有在R1位具有烷基链的美芬妥英和乙妥英，在300μM时能强烈激活hPXR。在R2和R3位均含有苯基或甲基苯基的苯妥英和5-（4-甲基苯基）-5-苯基乙内酰脲，也可激活hPXR，而5-（4-羟基苯基）-5-苯基乙内酰脲则不能激活该受体。这些结果表明，R1位存在烷基链以及R2和R3位存在庞大的疏水部分是乙内酰脲类药物激活hPXR的重要因素。对于大环内酯类抗生素，三乙酰竹桃霉素而非竹桃霉素，显示出对hPXR的显著激活。因此，竹桃霉素的三乙酸酯化可能会增加其疏水性并增强对hPXR的激活。这些发现表明，配体的疏水性以及氢键受体与疏水基团之间的适当距离对于hPXR激活很重要。
