Planta Med 2006; 72(6): 527-532
DOI: 10.1055/s-2006-931558
Original Paper
Pharmacology
© Georg Thieme Verlag KG Stuttgart · New York

Mechanism-Based Inhibition of Human Liver Microsomal Cytochrome P450 2D6 (CYP2D6) by Alkamides of Piper nigrum

 Subehan1 , Tepy Usia1 , Shigetoshi Kadota1 , Yasuhiro Tezuka1 , 2
  • 1Institute of Natural Medicine, University of Toyama, Toyama, Japan
  • 221st Century COE Program, University of Toyama, Toyama, Japan
Further Information

Publication History

Received: September 30, 2005

Accepted: December 8, 2005

Publication Date:
28 April 2006 (online)

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 (k inact and K I) were 0.028 min-1 and 0.23 μM for 15 and 0.064 min-1 and 0.71 μM 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.

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Dr. Yasuhiro Tezuka

Institute of Natural Medicine

University of Toyama

2630-Sugitani

Toyama 930-0194

Japan

Phone: +81-76-434-7627

Fax: +81-76-434-5059

Email: tezuka@inm.u-toyama.ac.jp