In vitro glutathione conjugation of methyl iodide in rat, rabbit, and human blood and tissues

Methyl iodide (Mel) is an intermediate in the manufacture of some pesticides and pharmaceuticals, and is under review for US registration as a non-ozone depleting alternative for methyl bromide for pre-plant soil fumigation. Mel is primarily metabolized via conjugation with glutathione (GSH), with further metabolism to S-methyl cysteine and methanethiol. To facilitate extrapolations of animal pharmacokinetic data to humans, rate constants for the GSH metabolism of Mel were determined in cytosols prepared from the liver and kidneys of rats, human donors, female rabbits, and rabbit fetuses, from rabbit olfactory and respiratory epithelium, and from rabbit and rat blood using a headspace vial equilibration technique and two-compartment mathematical model. Mel was metabolized in liver and kidney from adults of all three species, but metabolism was not detectable in fetal rabbit kidney. Maximal metabolic rates (V(max)) were similar in liver from rat and human donors (similar to 40 and 47 nmol/min/mg, respectively) whereas the V(max) rates in kidney cytosols varied approximately three-fold between the three species. No difference was observed in the loss of Mel from active and inactive whole blood from either rats or rabbits. The metabolism in olfactory and respiratory epithelial cytosol had Michaelis-Menten constant (K(m)) values that were several times higher than for any other tissue, suggesting essentially first-order metabolism in the nose. The metabolism of Mel in human liver cytosol prepared from five individual donors indicated two potential populations, one high affinity/low capacity and one with a lower affinity but higher capacity.