PT  - JOURNAL ARTICLE
AU  - Kobayashi, Kaoru
AU  - Yamagami, Saeko
AU  - Higuchi, Tomoaki
AU  - Hosokawa, Masakiyo
AU  - Chiba, Kan
TI  - KEY STRUCTURAL FEATURES OF LIGANDS FOR ACTIVATION OF HUMAN PREGNANE X RECEPTOR
AID  - 10.1124/dmd.32.4.468
DP  - 2004 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 468--472
VI  - 32
IP  - 4
4099  - http://dmd.aspetjournals.org/content/32/4/468.short
4100  - http://dmd.aspetjournals.org/content/32/4/468.full
SO  - Drug Metab Dispos2004 Apr 01; 32
AB  - 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 μM. 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. The American Society for Pharmacology and Experimental Therapeutics