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

1. The oxidative metabolism of 4-iodoanisole (1) by liver microsomes from beta-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 H2(18)O, 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 ferry moiety on the aromatic ring followed by reductive cleavage of the C-iodine bond, with electrons coming from P450 reductase.