Rietjens I M, Vervoort J
Department of Biochemistry, Agricultural University, Wageningen, The Netherlands.
Chem Biol Interact. 1991;77(3):263-81. doi: 10.1016/0009-2797(91)90036-7.
Metabolism and bioactivation of fluoroanilines was studied both in vitro in microsomal systems and in vivo. 4-Fluoroaniline and pentafluoroaniline and their non-para fluorinated analogues were used as the model compounds. Special attention was focussed on bioactivation to reactive benzoquinoneimines. Cytochrome P-450 dependent monooxygenation at a non-fluorinated para position in (fluoro)aniline derivatives proceeds by formation of the para hydroxylated derivative as the primary metabolite. Monooxygenation at a fluorinated para position in an aniline derivative, however, proceeds by formation of fluoride anion and the reactive benzoquinoneimine as primary reaction products. Thus, for fluoroanilines with a fluorine substituent at the para position bioactivation to the reactive benzoquinoneimine can be a direct result of the cytochrome P-450 dependent conversion. In systems containing NAD(P)H and/or other reducing equivalents part of the benzoquinoneimine can be chemically reduced to give the corresponding 4-hydroxyaniline. In vivo this reduced form of the metabolite can be sulphated or glucuronidated and excreted into urine. The results obtained point to increased chances of bioactivation for aniline derivatives with a fluorinated para position as compared to their non-para fluorinated analogues, both in vitro but also in vivo.
