Microsomal metabolism of fluoroanilines.
1. The microsomal, cytochrome P-450-dependent metabolism of fluoroanilines was studied using 19F-n.m.r. and also by a chemical assay for the hydroxy derivatives. 2. 2-Fluoro- and 3-fluoroaniline were preferentially hydroxylated at the para-position. 3. 4-Fluoroaniline was both p- and o-hydroxylated to a significant extent. 4. p-Hydroxylation of 4-fluoroaniline resulted in defluorination and formation of p-hydroxyaniline, and was not accompanied by an NIH-shift to give 4-hydroxy-3-fluoroaniline. 5. Liver microsomes from dexamethasone-pretreated rats demonstrated a relatively high contribution of defluorination to the total conversion of the fluoroanilines. This indicates that these microsomes contain a dexamethasone-inducible, NADPH-dependent factor, maybe cytochrome P-450 p (P450 IIIA1), which is especially effective in reductive dehalogenation of the fluoroanilines. 6. For 4-fluoroaniline it could be demonstrated that this relatively high dehalogenation by the dexamethasone-induced enzyme was not accompanied by an increased hydroxylation at the defluorinated position. Obviously, dehalogenation and hydroxylation are not strictly coupled processes. 7. p-Hydroxylation of all fluoroanilines was significantly increased per nmol of cytochrome P-450 when liver microsomes from isosafrole-, 3-methylcholanthrene-, or acetone-treated rats were used, indicating high activity of cytochrome P-450 isoenzymes d (P450 IA2) and j (P450 IIE1) for hydroxylation of fluoroanilines.
Rietjens
I M
IM
Department of Biochemistry, Agricultural University, Wageningen, The Netherlands.
Vervoort
J
J
D000814:Aniline Compounds / Q000378:metabolism*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D006900:Hydroxylation; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000814:Aniline Compounds; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases