Fluorobenzo[a]pyrenes as probes of the mechanism of cytochrome P450-catalyzed oxygen transfer in aromatic oxygenations

P.P.J. Mulder, P. Devanesan, K. van Alem, G. Lodder, E.G. Rogan, E.L. Cavalieri

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)

Abstract

Fluoro substitution of benzo[a]pyrene (BP) has been very useful in determining the mechanism of cytochrome P450-catalyzed oxygen transfer in the formation of 6-hydroxyBP (6-OHBP) and its resulting BP 1,6-, 3,6-, and 6,12-diones. We report here the metabolism of 1-FBP and 3-FBP, and PM3 calculations of charge densities and bond orders in the neutral molecules and radical cations of BP, 1-FBP, 3-FBP, and 6-FBP, to determine the mechanism of oxygen transfer for the formation of BP metabolites. 1-FBP and 3-FBP were metabolized by rat liver microsomes. The products were analyzed by HPLC and identified by NMR. Formation of BP 1,6-dione and BP 3,6-dione from 1-FBP and 3-FBP, respectively, can only occur by removal of the fluoro ion from C-1 and C-3, respectively, via one-electron oxidation of the substrate. The combined metabolic and theoretical studies reveal the mechanism of oxygen transfer in the P450-catalyzed formation of BP metabolites. Initial abstraction of a ¿ electron from BP by the [Fe4+=O]+¿ of cytochrome P450 affords BP+¿. This is followed by oxygen transfer to the most electropositive carbon atoms, C-6, C-1, and C-3, with formation of 6-OHBP (and its quinones), 1-OHBP, and 3-OHBP, respectively, or the most electropositive 4,5-, 7,8-, and 9,10- double bonds, with formation of BP 4,5-, 7,8-, or 9,10-oxide.
Original languageEnglish
Pages (from-to)734-745
JournalFree Radical Biology and Medicine
Volume34
Issue number6
DOIs
Publication statusPublished - 2003

Keywords

  • one-electron oxidation
  • rat-liver microsomes
  • radical cations
  • horseradish-peroxidase
  • semiempirical methods
  • mouse skin
  • benzo<a>pyrene
  • dna
  • identification
  • metabolism

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