QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.107.016584v1 35/10/1759    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yoo, H. H. Articles by Kim, D.-H. Search for Related Content PubMed PubMed Citation Articles by Yoo, H. H. Articles by Kim, D.-H.

Mechanism-Based Inactivation of Cytochrome P450 2A6 by Decursinol Angelate Isolated from Angelica Gigas

Bioanalysis and Biotransformation Research Center (H.H.Y., M.W.L., D.-H.K.), Korea Institute of Science and Technology, Chungryang, Seoul, Korea; College of Pharmacy (Y.C.K.), Seoul National University, Seoul, Korea; and School of Biological Sciences and Technology (C.-H.Y.), Chonnam National University, Gwangju, Korea

The inhibition of CYP2A6 by decursinol angelate, a pyranocoumarin isolated from Angelica gigas roots, was examined in human liver microsomes and recombinant CYP2A6. Decursinol angelate moderately inhibited coumarin 7-hydroxylation, but a 20-min preincubation with microsomes and NADPH significantly increased its inhibitory effect (IC₅₀; >20 versus 4.4 µM). A similar inhibition pattern was observed in nicotine C oxidation, which is also one of the prototype reactions of CYP2A6. Inactivation by decursinol angelate was selective for CYP2A6 and characterized by K_I values of 0.99 and 2.42 µM and the k_inact values of 0.136 and 0.053 min^-1 in microsomes and recombinant CYP2A6, respectively. This inactivation was not protected or restored by nucleophiles, reactive oxygen scavengers, or extensive dialysis but was inhibited by the addition of a competitive CYP2A6 inhibitor, pilocarpine. Furthermore, incubation of CYP2A6 with decursinol angelate in the presence of NADPH resulted in a loss of the spectral CYP2A6 content. An in vitro metabolism study revealed that CYP2A6 oxidized decursinol angelate to the dihydrodiol metabolite, presumably via an epoxide intermediate that might be responsible for the inactivation of CYP2A6. These results collectively demonstrated that decursinol angelate inactivated CYP2A6 in a mechanism-based mode.