Bioactivation of 4-fluorinated anilines to benzoquinoneimines as primary reaction products.
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.
Rietjens
I M
IM
Department of Biochemistry, Agricultural University, Wageningen, The Netherlands.
Vervoort
J
J
D000814:Aniline Compounds / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism*; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007097:Imines / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D005464:Fluorobenzenes; D005466:Fluorocarbons
D000814:Aniline Compounds; D016227:Benzoquinones; D003577:Cytochrome P-450 Enzyme System; D007097:Imines; D009249:NADP; C064299:1,4-benzoquinoneimine; C043455:4-fluoroaniline; C068134:2,3,4,5,6-pentafluoroaniline; D005464:Fluorobenzenes; D005466:Fluorocarbons