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Mechanism-based inactivation of cytochrome P450 3A4 by methylenedioxyphenyl lignans from Aconthoponox chiisonensis

Title
Mechanism-based inactivation of cytochrome P450 3A4 by methylenedioxyphenyl lignans from Aconthoponox chiisonensis
Author
유혜현
Keywords
Acanthopanax chiisanensis; Araliaceae; methylenedioxyphenyl lignans; CYP3A4; mechanism-based inactivation
Issue Date
2008-06
Publisher
GEORG THIEME VERLAG KG
Citation
PLANTA MEDICA, v. 74, No. 8, Page. 822-827
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(1) values of 2.4, 1.6, and 2.2 mu M 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.
URI
https://www.thieme-connect.de/DOI/DOI?10.1055/s-2008-1074556http://repository.hanyang.ac.kr/handle/20.500.11754/104676
ISSN
0032-0943
DOI
10.1055/s-2008-1074556
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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