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

Patrick P J Mulder, Prabu Devanesan, Kaj Van Alem, Gerrit Lodder, Eleanor G Rogan, Ercole Cavalieri

Research output: Contribution to journalArticle

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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 π 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 (US)
Pages (from-to)734-745
Number of pages12
JournalFree Radical Biology and Medicine
Volume34
Issue number6
DOIs
Publication statusPublished - Mar 15 2003

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Keywords

  • Benzo[a]pyrene radical cation
  • Cytochrome P450
  • Fluorobenzo[a]pyrenes
  • One-electron oxidation
  • Oxygen transfer
  • PM3 calculations

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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