title: Mechanism-based inhibition of CYP3A4 by constituents of Zingiber aromaticum.
abstract: Sixteen compounds isolated from Zingiber aromaticum and showing concentration-dependent inhibition with IC50 values less than 100 microM, were analyzed for their possibility of time-, concentration-, and NADPH-dependent inhibition of CYP3A4 and four were analyzed for CYP2D6. All seven kaempferol glycosides and two kaempferol derivatives (4, 5, 8-14) appear to be the mechanism-based inhibitors of CYP3A4 enzyme in which the inhibition is irreversible and driven by the catalytic process. The other compounds showed no NADPH-dependent inhibition or reversible inhibition, and thus do not appear to be mechanism-based inhibitors. K(I) values for compounds 4, 5, 8-14 were in the range of 2.21-27.01 microM, whereas the k(inact) values were 0.23-0.65 min(-1). Kaempferol-3-O-(2,3,4-tri-O-acetyl-alpha-L-rhamnopyranoside) (5) was found to be the most potent CYP3A4 inactivator with K(I) and k(inact) values of 2.21 microM and 0.45 min(-1), respectively.
authors.affiliation: Department of Natural Products Chemistry, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Sugitani, Toyama, Japan.
authors.forename: Tepy
authors.initials: T
authors.lastname: Usia
authors.forename: Tadashi
authors.initials: T
authors.lastname: Watabe
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Kadota
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tezuka
mesh_terms: D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology; D030521:Zingiberaceae
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D010936:Plant Extracts; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human