title: Hyperforin and its analogues inhibit CYP3A4 enzyme activity.
abstract: Literature indicates that herb-drug interaction of St. John's wort is largely due to increased metabolism of the co-administered drugs that are the substrates of cytochrome P450 (CYP) 3A4 enzyme, alteration of the activity and/or expression of the enzyme. The major St. John's wort constituents, acylphloroglucinols, were evaluated for their effects on CYP3A4 enzyme activity to investigate their roles in herb-drug interaction. Hyperforin and four oxidized analogues were isolated from the plant and fully characterized by mass spectral and NMR analysis. These acylphloroglucinols inhibited activity of CYP3A4 enzyme potently in the fluorometric assay using the recombinant enzyme. Furoadhyperforin (IC(50) 0.072 microM) was found to be the most potent inhibitor of CYP3A4 enzyme activity, followed by furohyperforin isomer 1 (IC(50) 0.079 microM), furohyperforin isomer 2 (IC(50) 0.23 microM), hyperforin (IC(50) 0.63 microM) and furohyperforin (IC(50) 1.3 microM). As the acylphloroglucinols are potent inhibitors of the CYP3A4 enzyme, their modulation of the enzyme activity is unlikely to be involved in increased drug metabolism by St. John's wort.
authors.affiliation: Pharmaceutical Chemistry, Faculty of Pharmacy, University of Sydney, Building A15, Science Road, Sydney, NSW 2006, Australia.
authors.forename: Ju-young
authors.initials: JY
authors.lastname: Lee
authors.forename: Rujee K
authors.initials: RK
authors.lastname: Duke
authors.forename: Van H
authors.initials: VH
authors.lastname: Tran
authors.forename: James M
authors.initials: JM
authors.lastname: Hook
authors.forename: Colin C
authors.initials: CC
authors.lastname: Duke
mesh_terms: D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D020902:Hypericum / Q000737:chemistry*; D015394:Molecular Structure; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D013729:Terpenes / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D001643:Bridged Bicyclo Compounds; D065607:Cytochrome P-450 Enzyme Inhibitors; D013729:Terpenes; D003577:Cytochrome P-450 Enzyme System; D010696:Phloroglucinol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C001654:hyperforin