Microsomal metabolism of fluoroanilines

Abstract

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.