title: Cytochrome P450 2D6 (CYP2D6) inhibitory constituents of Catharanthus roseus.
abstract: The MeOH-soluble fraction of the water extract of Catharanthus roseus from Indonesia, having shown potent inhibitory activity on the metabolism mediated by CYP2D6, was subjected to activity-guided isolation to yield two triterpenes, ursolic acid (1) and oleanolic acid (2), and three alkaloids, vindoline (3), ajmalicine (4), and serpentine (5). The isolated compounds were tested for their inhibitory activity on the metabolism mediated by CYP3A4 or CYP2D6 using [N-methyl-14C]erythromycin or [O-methyl-14C]dextromethorphan as a substrate, respectively. Ajmalicine (4) and serpentine (5) showed very potent inhibitory activity against CYP2D6 with IC50 values of 0.0023 and 3.51 microM, respectively. All isolated compounds showed weak or no inhibition against CYP3A4. On time-, concentration-, and NADPH-dependent assay, serpentine (5) appear to be the mechanism-based inhibitor for CYP2D6 enzyme in which the inhibition was irreversible and driven by catalytic process. K(I) and k(inact) values for serpentine (5) were 0.148 microM and 0.090 min-1, respectively. On the other hand, ajmalicine (4) showed no time-dependent inhibition or reversible inhibition, and thus appear to be not mechanism-based inhibitor.
authors.affiliation: Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 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: D030008:Catharanthus; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D035261:Plant Components, Aerial; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D010936:Plant Extracts; D019389:Cytochrome P-450 CYP2D6