OCCURRENCE OF THE NIH SHIFT UPON THE CYTOCHROME P450-CATALYZED IN-VIVO AND IN-VITRO AROMATIC RING HYDROXYLATION OF FLUOROBENZENES

The in vivo cytochrome P450-catalyzed aromatic hydroxylation of a seri es of fluorobenzenes was investigated with special emphasis on the imp ortance of the fluorine NIH shift. The results obtained demonstrate a minor role for the NIH shift in the metabolism of the fluorobenzenes t o phenolic metabolites in control male Wistar rats. These in vivo resu lts could indicate that (1) the NIH shift is an inherently minor proce ss for fluorine substituents or (2) it is a potentially significant pr ocess but the presumed epoxide that leads to formation of the NIH-shif ted metabolite is lost to an alternative metabolic pathway. In contras t to the in vivo data, in vitro experiments showed a significant amoun t of an NIH-shifted metabolite for 1,4-difluorobenzene. This result el iminates the explanation that the NIH shift is an inherently minor pro cess for fluorine substituents. Results of additional experiments pres ented in this paper show that the reduced tendency of fluorine-substit uted benzenes to undergo an NIH shift in vivo can-at least in part-be ascribed to the possible existence of alternative pathways for metabol ism of the epoxide, such as, for example, GSH conjugation, being more efficient for fluorinated than chlorinated arene oxides.