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.