Planta Med 2008; 74(8): 822-827
DOI: 10.1055/s-2008-1074556
Pharmacology
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Methylenedioxyphenyl Lignans from Acanthopanax chiisanensis

Hye Hyun Yoo1 , Sang-Hyun Lee2 , Changbae Jin1 , Dong-Hyun Kim1
  • 1Doping Control Center, Korea Institute of Science and Technology, Seoul, Korea
  • 2Department of Applied Plant Science, College of Industrial Science, Chung-Ang University, Gyeonggi-do, Korea
Further Information

Publication History

Received: March 7, 2008 Revised: April 11, 2008

Accepted: April 22, 2008

Publication Date:
18 June 2008 (online)

Abstract

The purpose of this investigation is to characterize the inhibition of CYP3A4 by methylenedioxyphenyl lignans isolated from Acanthopanax chiisanensis. Inhibition of CYP3A4 by three methylenedioxyphenyl lignans, avinin, helioxanthin, and 3-(3″,4″-dimethoxybenzyl)-2-(3′,4′-methylenedioxybenzyl)butyrolactone was time-, concentration-, and NADPH-dependent and characterized by K I values of 2.4, 1.6, and 2.2 μM and k inact values of 0.030, 0.043, and 0.047 min−1, respectively. The inhibition of CYP3A4 activity by these lignans was suppressed in the presence of a competitive CYP3A4 substrate, ketoconazole. Addition of nucleophiles or reactive oxygen scavenger and dialysis did not prevent inactivation of CYP3A4 by the Acanthopanax lignans. The loss of CYP3A4 enzymatic activity resulting from incubation with the Acanthopanax lignans was accompanied with a spectral loss of CYP3A4. These results collectively demonstrate that savinin, helioxanthin and 3-(3″,4″-dimethoxybenzyl)-2-(3′,4′-methylenedioxybenzyl)butyrolactone from A. chiisanensis inactivate CYP3A4 in a mechanism-based mode.

Abbreviations

CYP: cytochrome P450

CAP3A4: cytochrome P450 3A4

KI: inhibitor concentration required for a half-maximal inactivation

Kinact: maximal rate constant of the inactivation

P450: cytochrome P450

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Dr. Changbae Jin

Doping Control Center

Korea Institute of Science and Technology

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