title: Role of cytochrome P450 and UDP-glucuronosyltransferases in metabolic pathway of homoegonol in human liver microsomes.
abstract: Homoegonol is being evaluated for the development of a new antiasthmatic drug. Based on a pharmacokinetic study of homoegonol in rats, homoegonol is almost completely eliminated via metabolism, but no study on its metabolism has been reported in animals and humans. Incubation of homoegonol in human liver microsomes in the presence of the reduced form of nicotinamide adenine dinucleotide phosphate and UDP-glucuronic acid resulted in the formation of five metabolites: 4-O-demethylhomoegonol (M1), hydroxyhomoegonol (M2 and M3), 4-O-demethylhomoegonol glucuronide (M4), and homoegonol glucuronide (M5). We characterized the cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes responsible for homoegonol metabolism using human liver microsomes, and cDNA-expressed CYP and UGT enzymes. CYP1A2 played a more prominent role than CYP3A4 and CYP2D6 in the 4-O-demethylation of homoegonol to M1. CYP3A4 was responsible for the hydroxylation of homoegonol to M2. The hydroxylation of homoegonol to M3 was insufficient to characterize CYP enzymes. Glucuronidation of homoegonol to M5 was mediated by UGT1A1, UGT1A3, UGT1A4, and UGT2B7 enzymes, whereas M4 was formed from 4-O-demethylhomoegonol by UGT1A1, UGT1A8, UGT1A10, and UGT2B15 enzymes.
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Republic of Korea.
authors.forename: Soon Sang
authors.initials: SS
authors.lastname: Kwon
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Republic of Korea.
authors.forename: Ju Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Republic of Korea.
authors.forename: Hyeon-Uk
authors.initials: HU
authors.lastname: Jeong
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Republic of Korea.
authors.forename: Kyung-Seop
authors.initials: KS
authors.lastname: Ahn
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Republic of Korea.
authors.forename: Sei-Ryang
authors.initials: SR
authors.lastname: Oh
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Republic of Korea. Electronic address: sianalee@catholic.ac.kr.
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
mesh_terms: D000840:Anisoles / Q000378:metabolism*; D001572:Benzofurans / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation / Q000502:physiology; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism*; D009249:NADP / Q000378:metabolism
chemical_list: D000840:Anisoles; D001572:Benzofurans; D020719:Glucuronides; C000597557:homoegonol; D009249:NADP; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D014453:Glucuronosyltransferase
keywords: 4-O-demethylation; Cytochrome P450s; Glucuronidation; Homoegonol; Human liver microsomes; UDP-Glucuronosyltransferases