Bioconversion of deoxypodophyllotoxin into epipodophyllotoxin in E-coli using human cytochrome P450 3A4

Nikolay P. Vasilev, Mattijs K. Julsing, Albert Koulman, Cailean Clarkson, Herman J. Woerdenbag, Iliana Ionkova, Rein Bos, Jerzy W. Jaroszewski, Oliver Kayser*, Wim J. Quax

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Biotransformation of deoxypodophyllotoxin to epipodophyllotoxin by three major human hepatic enzymes, CYP1A2, CYP2C9 and CYP3A4, heterologously expressed in E coli DH5 alpha, was investigated. It was shown that CYP3A4 catalysed the hydroxylation of deoxypodophyllotoxin into epipodophyllotoxin in yields up to 90%. The structure of the metabolite was determined using HPLC-MS and HPLC-SPE-NMR. techniques. There was no detectable production of epipodophyllotoxin or podophyllotoxin by CYP1A2 and CYP2C9 enzymes. The CYP3A4 enzyme shows a distinctly different reactivity to deoxypodophyllotoxin compared to the semi-synthetic derivatives etoposide and teniposide, which are degraded by 3-O-demethylation. These findings demonstrate a novel system for the production of 2,7'-cyclolignans, starting from the easily accessible deoxypodophyllotoxin. (c) 2006 Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)383-393
Number of pages11
JournalJournal of Biotechnology
Volume126
Issue number3
DOIs
Publication statusPublished - 10-Nov-2006

Keywords

  • Podophyllum
  • cytochrome p450
  • podophyllotoxin
  • HPLC-SPE-NMR
  • HPLC-MS
  • BETA-D-GLUCOSIDE
  • CELL-CULTURES
  • LINUM-FLAVUM
  • ANTHRISCUS-SYLVESTRIS
  • LIVER-MICROSOMES
  • PODOPHYLLOTOXIN
  • DEMETHYLATION
  • METABOLISM
  • CONVERSION
  • CONGENERS

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