Chemico-Biological Interactions 1991-01-01

Bioactivation of 4-fluorinated anilines to benzoquinoneimines as primary reaction products.

I M Rietjens, J Vervoort

Index: Chem. Biol. Interact. 77(3) , 263-81, (1991)

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Abstract

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.