Key structural features of ligands for activation of human pregnane X receptor.

Article Details

Citation

Kobayashi K, Yamagami S, Higuchi T, Hosokawa M, Chiba K

Key structural features of ligands for activation of human pregnane X receptor.

Drug Metab Dispos. 2004 Apr;32(4):468-72.

PubMed ID
15039302 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
EthotoinNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Activator
Details
MephenytoinNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Activator
Details
MethylphenobarbitalNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Activator
Details
PentobarbitalNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Activator
Details
PhenobarbitalNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Activator
Details
PhenytoinNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Not AvailableDetails
TroleandomycinNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Activator
Details