title: Mechanism-based CYP2D6 inactivation by acridone alkaloids of Indonesian medicinal plant Lunasia amara.
abstract: Fourteen acridone alkaloids isolated from Lunasia amara Blanco were tested for their mechanism-based inhibition on human liver microsomal dextromethorphan O-demethylation activity, a prototype marker for cytochrome P450 2D6 (CYP2D6). Among the 14 compounds, 5-hydroxygraveroline (1), 8-methoxyifflaiamine (2), lunamarine (3), and lunine (12) increased their inhibitory activity with increasing preincubation time. Then, we further examined the possibility of mechanism-based inhibition on 5-hydroxygraveroline (1) and lunamarine (3), which showed the potent inhibition. Further investigations on 1 and 3 showed that the characteristic time- and concentration-dependent inhibition, which required a catalytic step with NADPH, was not protected by nucleophiles, and was decreased by the presence of a competitive inhibitor. Thus, 1 and 3 were concluded as mechanism-based inactivators of CYP2D6.
authors.affiliation: Institute of Natural Medicine, University of Toyama, 2630-Sugitani, Toyama 930-0194, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Takahashi
authors.lastname: Subehan
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Kadota
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tezuka
mesh_terms: D000166:Acridines / Q000494:pharmacology*; D054831:Acridones; D000470:Alkaloids / Q000494:pharmacology*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003915:Dextromethorphan / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D041743:Herb-Drug Interactions; D006801:Humans; D007214:Indonesia; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008745:Methylation; D008861:Microsomes / Q000187:drug effects; D009249:NADP / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D010946:Plants, Medicinal / Q000737:chemistry; D027821:Rutaceae / Q000737:chemistry*
chemical_list: D000166:Acridines; D054831:Acridones; D000470:Alkaloids; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D010936:Plant Extracts; D009249:NADP; C041300:acridone; D003915:Dextromethorphan