title: Occurrence of the NIH shift upon the cytochrome P450-catalyzed in vivo and in vitro aromatic ring hydroxylation of fluorobenzenes.
abstract: The in vivo cytochrome P450-catalyzed aromatic hydroxylation of a series of fluorobenzenes was investigated with special emphasis on the importance of the fluorine NIH shift. The results obtained demonstrate a minor role for the NIH shift in the metabolism of the fluorobenzenes to phenolic metabolites in control male Wistar rats. These in vivo results could indicate that (1) the NIH shift is an inherently minor process for fluorine substituents or (2) it is a potentially significant process but the presumed epoxide that leads to formation of the NIH-shifted metabolite is lost to an alternative metabolic pathway. In contrast to the in vivo data, in vitro experiments showed a significant amount of an NIH-shifted metabolite for 1,4-difluorobenzene. This result eliminates the explanation that the NIH shift is an inherently minor process for fluorine substituents. Results of additional experiments presented in this paper show that the reduced tendency of fluorine-substituted benzenes to undergo an NIH shift in vivo can-at least in part-be ascribed to the possible existence of alternative pathways for metabolism of the epoxide, such as, for example, GSH conjugation, being more efficient for fluorinated than chlorinated arene oxides.
authors.affiliation: Departments of Biochemistry and Molecular Physics, Agricultural University, Dreijenlaan 3, 6703 HA Wageningen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Koerts
authors.forename: A E
authors.initials: AE
authors.lastname: Soffers
authors.forename: J
authors.initials: J
authors.lastname: Vervoort
authors.forename: A
authors.initials: A
authors.lastname: De Jager
authors.forename: I M
authors.initials: IM
authors.lastname: Rietjens
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D005464:Fluorobenzenes / Q000737:chemistry* / Q000652:urine; D005978:Glutathione / Q000494:pharmacology; D006900:Hydroxylation; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000302:isolation & purification / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014250:Trichosporon / Q000201:enzymology
chemical_list: D005464:Fluorobenzenes; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C022336:phenol 2-monooxygenase; D005978:Glutathione