title: Mechanism-based inhibition of human liver microsomal cytochrome P450 2D6 (CYP2D6) by alkamides of Piper nigrum.
abstract: Nineteen alkamides isolated from Piper nigrum L. were tested for their mechanism-based inhibition on human liver microsomal dextromethorphan O-demethylation activity, a prototype marker for cytochrome P450 2D6 (CYP2D6). All compounds increased their inhibitory activity with increasing preincubation time. Among them, 15 and 17 showed more than 50 % decrease of the CYP2D6 residual activity after 20 min preincubation. Further investigations on 15 and 17 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. The kinetic parameters for inactivation (kinact and KI) were 0.028 min-1 and 0.23 microM for 15 and 0.064 min-1 and 0.71 microM for 17, respectively, which were stronger than the known mechanism-based inhibitor, paroxetine (a positive control). Thus, 15 and 17 are potent mechanism-based inhibitors of CYP2D6.
authors.affiliation: Institute of Natural Medicine, University of Toyama, Toyama, Japan.
authors.lastname: Subehan
authors.forename: Tepy
authors.initials: T
authors.lastname: Usia
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Kadota
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tezuka
mesh_terms: D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004305:Dose-Response Relationship, Drug; D005638:Fruit; D041743:Herb-Drug Interactions; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D008517:Phytotherapy; D029222:Piper nigrum; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000577:Amides; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D010936:Plant Extracts; D019389:Cytochrome P-450 CYP2D6