title: In vitro metabolism of an estrogen-related receptor γ modulator, GSK5182, by human liver microsomes and recombinant cytochrome P450s.
abstract: GSK5182 (4-[(Z)-1-[4-(2-dimethylaminoethyloxy)phenyl]-hydroxy-2-phenylpent-1-enyl]phenol) is a specific inverse agonist for estrogen-related receptor γ, a member of the orphan nuclear receptor family that has important functions in development and homeostasis. This study was performed to elucidate the metabolites of GSK5182 and to characterize the enzymes involved in its metabolism. Incubation of human liver microsomes with GSK5182 in the presence of NADPH resulted in the formation of three metabolites, M1, M2 and M3. M1 and M3 were identified as N-desmethyl-GSK5182 and GSK5182 N-oxide, respectively, on the basis of liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. M2 was suggested to be hydroxy-GSK5182 through interpretation of its MS/MS fragmentation pattern. In addition, the specific cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) isoforms responsible for GSK5182 oxidation to the three metabolites were identified using a combination of correlation analysis, chemical inhibition in human liver microsomes and metabolism by expressed recombinant P450 and FMO isoforms. GSK5182 N-demethylation and hydroxylation is mainly mediated by CYP3A4, whereas FMO1 and FMO3 contribute to the formation of GSK5182 N-oxide from GSK5182. The present data will be useful for understanding the pharmacokinetics and drug interactions of GSK5182 in vivo.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 702-701, Korea.
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Joo
authors.forename: Zhexue
authors.initials: Z
authors.lastname: Wu
authors.forename: Boram
authors.initials: B
authors.lastname: Lee
authors.forename: Jong Cheol
authors.initials: JC
authors.lastname: Shon
authors.forename: Taeho
authors.initials: T
authors.lastname: Lee
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Kim
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.forename: Seong Heon
authors.initials: SH
authors.lastname: Kim
authors.forename: Kwang-Hyeon
authors.initials: KH
authors.lastname: Liu
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004967:Estrogens; C583041:GSK5182; D007004:Hypoglycemic Agents; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; C425824:estrogen receptor gamma; D013629:Tamoxifen; D003577:Cytochrome P-450 Enzyme System
keywords: GSK5182; cytochrome P450; flavin-containing monooxygenase; microsomes; oxidation