Studies on the in vitro metabolism of methidathion by rat and mouse liver

Abstract

The in vitro metabolism of methidathion, S-[(5-methoxy-2-oxo-1,3,4-thiadiazol-3(2 H)-yl)methyl] O,O-dimethyl phosphorodithioate was studied in rat and mouse liver subcellular fractions. Similarly, the in vitro metabolism of the metabolites of methidathion, including desmethyl methidathion; the sulfide, 3-(methylthiomethyl)-5-methoxy-1,3,4-thiadiazol-2(3 H)-one; the sulfoxide, 3-(methylsulfinylmethyl)-5-methoxy-1,3,4-thiadiazol-2(3 H)-one; and the sulfone, 3-(methylsulfonylmethyl)-5-methoxy-1,3,4-thiadiazol-2(3 H)-one, was investigated in rat liver subcellular fractions. The major route of metabolism of methidathion in rat and mouse liver was via glutathione S-transferases and the predominant metabolite was desmethyl methidathion. The mixed-function oxidase system was also involved in the metabolism of methidathion. Four watersoluble metabolites characterized were desmethyl methidathion; the glutathione conjugate of the heterocyclic moiety of methidathion, S[(5-methoxy-2-oxo-1,3,4-thiadiazol-3(2 H)-yl] l-glutathione; the cysteinylglycine conjugate; and the cysteine conjugate. Chloroform-soluble metabolites identified were the oxygen analog of methidathion and methoxythiadiazolin. Desmethyl methidathion and the sulfone underwent no further degradation. Thioether oxidation of the sulfide to the sulfoxide was found to be the major reaction mediated by the FAD-dependent monooxygenase system. However, oxidation of the sulfoxide to the sulfone was mediated by the mixed-function oxidase system and appeared to be a minor pathway. The in vitro metabolism of methidathion by rat and mouse liver was qualitatively similar; however, a few quantitative interspecies differences were evident.