S-Methylation of O,O-Dialkyl Phosphorodithioic Acids:  O,O,S-Trimethyl Phosphorodithioate and Phosphorothiolate as Metabolites of Dimethoate in Mice

Abstract

O,O,S-Trimethyl phosphorodithioate and phosphorothiolate [(MeO)2P(S)SMe and (MeO)2P-(O)SMe, respectively are known from earlier studies to be impurities, delayed toxicants, and detoxication inhibitors in several major O,O-dimethyl phosphorodithioate insecticides. Our recent studies show extensive S-methylation of mono- and dithiocarbamic acids in mice, suggesting the possibility that phosphorodithioic acids such as (MeO)2P(S)SH might also undergo S-methylation. This possibility was examined in ip-treated mice with emphasis on the metabolites of dimethoate [(MeO)2P(S)SCH2C(O)NHMe], one of the most important organophosphorus insecticides. The urinary metabolites of dimethoate, which contains no P-SMe substituent, were found to include four compounds with P-SMe moieties identified by 31P NMR spectroscopy as MeO(HS)P(O)SMe, MeO(HO)P(O)SMe, (MeO)2P(S)SMe, and (MeO)2P-(O)SMe; the latter two compounds are also established by GC-MS as dimethoate metabolites in mouse urine, liver, kidney, and lung. Several approaches verified unequivocally that the previously unknown P-SMe metabolites in urine and tissues are due to in vivo S-methylation rather than to impurities. Studies with other O,O-dimethyl and O,O-diethyl phosphorodithioate insecticides established the analogous S-methylation pathway for ethion, malathion, phenthoate, phosalone, and phosmet in mice. Thus, metabolism of O,O-dialkyl phosphorodithioate insecticides in mammals is shown here for the first time to yield S-methyl phosphorodithioates and phosphorothiolates from in vivo S-methylation of the intermediate O,O-dialkyl phosphorodithioic acids.

Kinetic Analysis for Hydrolysis of Malathion by Carboxylesterase in Wheat Kernels

“…Such enzymatic degradation behavior is observed in mouse 18) and human. 15,18) Since there is no other enzymatic metabolite, such as O,O -dimethyl phosphorodithioic acid or O,Odimethyl phosphorothioic acid, which are produced in mouse 19) and human, 20) CE is the only malathion-degradable enzyme in wheat kernels.…”

Theoretical Study of31P NMR Chemical Shifts for Organophosphorus Esters, Their Anions and O,O-Dimethylthiophosphorate Anion with Metal Complexes

“…2,8 Furthermore, the 31 P NMR chemical shifts for OP pesticides show upfield shifts when the OP is coordinated to transition metals. 3,4,8 Similarly, in studies of the series of compounds Ia-d containing different X substituents on the meta and para positions of the phenyl moiety, it was found that electron withdrawing substituents lead to an upfield shift of the 31 P signal, pointing to a shielding effect on the P atom. 9 However, contrary wise, in studies of the alkyl and aryl phosphinate ester series IIa-c Hoz, Buncel and co-workers 10b found that electron-withdrawing substituents (X) induced downfield shifts in 31 P chemical shift, i.e.…”

“…2 To illustrate, interestingly, a literature survey showed that the 31 P NMR chemical shifts of structurally modified OP ester pesticides, replacing (RO)P=O by (RS)P =O, (RO)P=S and (RS)P=S functionalities, resulted in 31 P chemical shift changes by up to 100 ppm as summarized in Table 1. [3][4][5][6][7] In rationalizing such results one of the guiding principles that has come through theoretical and experimental studies is the concept of electronegativity, i.e. that increase in electron density of an atomic nucleus enhances its shielding, resulting in an upfield chemical shift.…”

Use of NMR techniques for toxic organophosphorus compound profiling

“…Mahajna et al [79] analyzed metabolism of O,O-dialkyl phosphorodithioate insecticides in mammals. Their study concerned with the possibility of S-methylation of phosphorodithioic acids such as (MeO) 2 P(S)SH, resulting in O,O,S-trimethyl compounds as metabolites.…”