title: Reaction pathways for biodehalogenation of fluorinated anilines.
abstract: Pathways for biodehalogenation of fluorinated aniline derivatives were investigated. Microsomal NADPH-dependent dehalogenation of fluoroanilines was shown to proceed by three different reaction pathways. The first route appeared to result in monooxygenation at a fluorinated position and release of the fluorine atom as a fluoride anion. The primary additional reaction product formed is the reactive quinoneimine, not the 4-hydroxyaniline. In NADPH-containing microsomal systems with 4-fluoro-substituted anilines, formation of the 4-hydroxyaniline derivative is observed because NADPH chemically reduces this quinoneimine metabolite. A second pathway for dehalogenation proceeds by protein binding of a fluoro-containing (semi)quinoneimine metabolite, the formation of which may result from the mono-oxygenase reaction (pathway 1) and/or from (re)oxidation of a hydroxyaniline metabolite by superoxide anion radicals produced by the microsomal system. This latter reaction pathway becomes more important with increasing number of fluoro-substituents in the fluoroaniline derivative. The higher ratio of fluoride anion formed to 4-hydroxyaniline derivative detected in incubations with liver microsomes from dexamethasone-treated rats, as compared to incubations with liver microsomes from control rats, can in part be explained by the higher production of superoxide anion radicals observed in the dexamethasone systems. The third mechanism was shown to proceed by formation of a hydroxylated metabolite that loses fluoride anion upon exposure to oxygen. The reactive intermediate formed upon oxygen exposure might be the semiquinoneimine which loses its fluorine atom as a fluoride anion upon dimerization or polymerization and/or protein binding. The fluorohydroxyanilines, in which the hydroxyl group is ortho or para with respect to the fluoro substituent, appear especially to be highly unstable and lose fluoride anion in the presence of oxygen. Finally, it is concluded that all three pathways for dehalogenation of fluorinated aniline derivatives are bioactivation pathways. The reactivity of the (semi)quinoneimines formed in these reactions is dependent on their substitution pattern and increases with increasing number of fluoro-substituents. Therefore, bioactivation for a series of fluorinated aniline derivatives, can be expected to vary with the substitution pattern and to increase with increasing number of halogen substituents.
authors: Department of Biochemistry, Agricultural University, Wageningen, The Netherlands.
authors: I M
authors: IM
authors: Rietjens
authors: B
authors: B
authors: Tyrakowska
authors: C
authors: C
authors: Veeger
authors: J
authors: J
authors: Vervoort
mesh_terms: D000814:Aniline Compounds / Q000378:metabolism*; D000818:Animals; D005461:Fluorine / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006900:Hydroxylation; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000814:Aniline Compounds; D011506:Proteins; D005461:Fluorine; D009249:NADP; D005978:Glutathione; D010100:Oxygen; C023650:aniline