Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

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Record number 343260
Title Fluorobenzo[a]pyrenes as probes of the mechanism of cytochrome P450-catalyzed oxygen transfer in aromatic oxygenations
Author(s) Mulder, P.P.J.; Devanesan, P.; Alem, K. van; Lodder, G.; Rogan, E.G.; Cavalieri, E.L.
Source Free Radical Biology and Medicine 34 (2003)6. - ISSN 0891-5849 - p. 734 - 745.
DOI https://doi.org/10.1016/S0891-5849(02)01374-6
Department(s) RIKILT - Analyse & OntwikkelingBU Microbiological & Chemical Food Analysis
Publication type Refereed Article in a scientific journal
Publication year 2003
Keyword(s) one-electron oxidation - rat-liver microsomes - radical cations - horseradish-peroxidase - semiempirical methods - mouse skin - benzo<a>pyrene - dna - identification - metabolism
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.
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