Oxidative and non-oxidative metabolism of 4-iodoanisole by rat liver microsomes

Abstract

1. The oxidative metabolism of 4-iodoanisole (1) by liver microsomes from β-naphthoflavone-treated rats yields 4-iodophenol (2) 2-iodo-5-methoxyphenol (3). 2-methoxy-5-iodophenol (4), 4-methoxyphenol (5), and 3-methoxyphenol (6) in relative yields of 5:2:4:1:1 respectively.

2. [3 5-²H₂]-1 was converted to the same five metabolites in the same proportions: formation of 2, 4 and 5 involved no loss of deuterium, but formation of 3 and 6 involved respectively 55 and 28% loss of one deuterium.

3. When metabolism of 1 was carried out in buffers containing D₂O or H₂¹⁸O, no incorporation of these isotopes into 2–6 could be detected. Nor was it possible to detect formation of iodinating intermediates derived from 1 by trapping with 2,6-dimethylphenol.

4. The P450-catalysed hydroxylative de-iodination of 1–5 and 6 is suggested to involve C-O bond formation via attack of the ferryl moiety on the aromatic ring followed by reductive cleavage of the C-iodine bond, with electrons coming from P450 reductase.