Phosphorothionate, oxidation

This process of aging is believed to be critical in the development of delayed neuropathy, after NTE has been phosphorylated by an OP (see Chapter 10, Section 10.2.4). It is believed that most, if not all, of the B-esterases are sensitive to inhibition by OPs because they, too, have reactive serine at their active sites. It is important to emphasize that the interaction shown in Fignre 2.11 occurs with OPs that contain an oxon group. Phosphorothionates, which contain instead a thion group, do not readily interact in this way. Many OP insecticides are phosphorothionates, but these need to be converted to phosphate (oxon) forms by oxidative desulfuration before inhibition of acetylcholinesterase can proceed to any significant extent (see Section 2.3.2.2). 

Data presentations should include the parent compound and all toxic transformation products. This is particularly important for oxidation of sulfide linkages to sulfoxides or sulfones. These products are often equally toxic to the parent with increased availability. Attention should also be given to oxidative desulfuration of phosphorothionate esters. 

Three different pathways are associated with the metabolism of disulfoton (I) oxidation of the thioether sulfur to produce sulfoxides and sulfones (2) oxidation of the thiono sulfur to produce the oxygen analogs and (3) hydrolysis of the P-S-C linkage to produce the corresponding phosphorothionate or phosphate (WHO 1976) (see Figure 2-3). These pathways have been elucidated from data obtained in humans exposed to disulfoton and from in vivo and in vitro metabolism studies in rats and mice. 

The discovery of prontosil was fortuitous and was not based on rationale design. There are a large number of pesticides which fall in the same category as prontosil, i.e., they are active by virtue of their susceptibility to metabolic or chemical modification to active intermediates. The classical example of an insecticide of this type is parathion, a phosphorothionate ester which in animals or plants is oxidatively desulfurated to the potent anticholinesterase paraoxon O). The insecticidal activity of parathion was known for several years before the purified material was shown to be a poor anticholinesterase and that metabolic activation to paraoxon was necessary for intoxication. 

Many organosulfur compounds undergo biological oxidation at the sulfur atom to yield products which have pronounced physiological activity or serve as intermediates in generating bioactive compounds. Three examples are the lachrymating agent in onions ( ) (1), the oxo intermediate ( ) in metabolic desulfuration of phosphorothionate insecticides to form potent cholinesterase inhibitors (2), and the sulfoxides QJ produced on metabolism of thiocarbamate herbicides (3). 

Torrents, A., and A. T. Stone, Oxide surface-catalyzed hydrolysis of carboxylate esters and phosphorothionate esters , Soil Sci. Soc. Am. J., 58, 738-745 (1994). 

What are the general formulas of phosphorothionate and phosphorodithioate esters How are the thiono and P=0 functional groups involved in these kinds of esters How are they used What is oxidative desulfuration and why is it significant with these kinds of compounds ... 

The ability to cleave off the leaving group by a process presumably hydrolytic has been detected in a number of OP-resistant species (Table X). In the tobacco budworm clear evidence for OP-resistance being associated with oxidative cleavage was obtained from the action of microsomes on the phosphorothionate chlorpyrifos... 

Desulfuration An important oxidation is the conversion of the P = S group of phosphorothion-ates to P = 0, the oxon form, increasing the intensity of ChE inhibition. 

S-containing phosphorothionate compounds. It is generally recognized that these phosphorothionate compounds are not active toxicants but rather protoxicants. Oxidation, which results in exchange of the doubly bonded sulfur for a doubly bonded oxygen, is necessary for conversion of the protoxicant phosphorothionate compounds to active neurotoxicants. 

Thiones (Ar2C=S) are oxidized to thiones 5-oxides (Ar2C=S=0) by A-sulfonyloxaziridine (78) (Scheme 14) <87JCS(Pl)l 113). The oxidation is fast and quantitative, exhibiting second-order kinetics. Thiocamphor 5-oxide (79) and thiofenchone 5-oxide (80) were prepared in 91% and 76% yield, respectively by oxidation of the corresponding thiones with (78b). Earlier attempts to prepare these materials with other oxidants resulted in low yields and the products were difficult to purify. Phosphorothionates (R2P(S)OPh) are oxidized to phosphates (R2P(0)0Ph) by A-sulfonyl-oxaziridines <88MI 112-01). 

The reactions show some typical oxidations of insecticides catalyzed by CYP enzymes. Carbofuran is hydroxylated to another active compound carbaryl is demethylated or hydroxylated and aldrin is epoxidated to diel-drin, which also has insecticidal properties. Phosphorothionates must be oxidized to the phosphates by CYP enzymes in order to become inhibitors of acetyl cholinesterase. Parathion-methyl is transformed to the oxon analogue, paraoxon-methyl, which is the toxic compound. It also can be demethylated to the inactive desmethyl-parathion-methyl. 

NITROPHENYL PHOSPHOROTHIONATE or DIETHYL p-NITROPHENYL THIONOPHOSPHATE (56-38-2) Combustible liquid (flash point 248°F/120°C). Strong oxidizers may cause fire and explosions. Rapidly hydrolyzed by alkalis. Mixture with endrin may be explosive. Attacks some plastics, rubber, or coatings. 

The desulfuration/dearylation reactions described previ-ou.sly are probably the most common of the CYP-mediated reactions on OP insecticides. However, the CYPs can also mediate the oxidative removal of one of the alkoxy groups, leaving, for exatnple, a monoalkyl phosphorothionate and the aldehyde (Appleton and Nakatsugawa, 1972). Since this reaction will prevent subsequent desulfuration, the dealkylation reaction is a detoxication. The dcmcthylation of methyl parathion to monorncthyl parathion and formaldehyde is illustrated in Fig. 2. 

The Ph2PS radical is produced by Jlf-irradiation of diphenylthiophos-phine, and under y-irradiation trichlorosilane brings about the desulphura-tion of phosphine sulphides to phosphines and of phosphorothionates to phosphites. Chloramine-T has been found to be a useful oxidant for distinguishing between a variety of structural units, particularly in phosphorus-sulphur compounds. ... 

Sex differences have been demonstrated in the toxicity of phosphorothionate pesticides to rats in vivo and in the oxidative capacity of liver slices from male and female rats in vitro. In studying the influence of various factors on the activation of azinphos-methyl and O-ethyl-O-phenyl-D-p-nitrophenylphos-phorothionate (EPN), the livers of male rats were found to be 2-3 times more active than those of females in converting these compounds to their oxo-analogues [47]. In young animals up to the age of 30 days, no difference is evident between males and females, but after 30 days the activity of the male liver rises while that of the female liver remains constant. Castration or administration of diethylstilboestrol prevents this rise in males, while admini-... 

Carcinogenic hydrocarbons have been reported to increase the activity of this oxidising enzyme system in immature males, adult females and partially hepatectomized adult males [47]. This involves the synthesis of new enzyme protein which may be prevented by ethionine, a competitive antagonist to the incorporation of methionine into new protein [48]. The microsomal enzyme inhibitor SKF 525A similarly prevents oxidation of the phosphoro-thionates, so reducing their toxicity [47], Similar observations on the influence of sex hormones, age and microsomal enzyme inducers on the toxicity of schradan [49, 50], parathion [51, 52], fenitrothion [53], EPN. 0-(4-methyl-7-hydroxycoumarin)-0,( -diethylphosphorothionate (E838) [51] and 0,0-diethyl-0-(3-methyl-4-methylthiophenyl)phosphorothionate (DMP) [54] in rats have been reported. 

Reduction of the toxicity of the phosphorothionate insecticide, EPN, to rats by nikethamide [135] is paralleled by a reduction in the cholinesterase inhibitory potency of this compound in vivo [136]. Nikethamide induces the synthesis of oxidative microsomal enzymes [137] concerned in the detoxication of EPN in both male and female rats [138]. Induction of these enzymes by the daily administration of phenobarbitone, 50 mg/kg for 5 days, reduces the acute toxicities of parathion, demeton-0, EPN, disulfoton, dioxathion. 

The relationship between the chemical structure and toxicity of various coumarin insecticides and anthelmintics are compiled (Table 3.13), and for comparison, some other related compounds are also tabulated. The mammalian toxicity of these compounds is moderate, and their selective action on insects is coimected with differences in metabolism. In mammals these chemicals are probably rapidly metabolised by hydrolysis between the aromatic and phosphate groups, whereas in insects by slow oxidation of the phosphorothionate to phos-... 

No effective replacement molecule for ZnDTP has been reported, to date. In an effort to understand why current replacement candidates are not sufficiently effective, we scrutinized the thermal chemistry of triphenyl phosphorothionate (TPPT) in oil by means of infrared and nuclear magnetic resonance spectroscopies. TPPT appeared to be both more thermally stable than ZnDTP (and therefore not activated under most conditions), as well as being a much less effective oxidation inhibitor — the original application of ZnDTP (2.39). 

Keywords Thermo-oxidative degradation /x Triphenyl phosphorothionate /xAshless anti-wear additive /x Low-SAPS additive /xFT-IR /xNMR... 

The same authors studied the thermal films produced by triphenyl phosphorothionate (TPPT) at 423 K. Also, in this case, the formation of short-chain ironfll) polyphosphate with a low amount of iron snlfafe was suggested [22]. In the tribotracks, short-chain ironfll) polyphosphate, iron sulfides, and sulfates were defected. Increasing sliding time induced an increase in the amormt of iron snUate. After 6 h, comparable amounts of iron snlfafe and phosphates were observed. These findings were explained by the authors with a decomposition temperature for triphenyl phoshoro-thionate of around 423 K. Following the adsorption, the thermal oxidative process took place after the breakage of the P=S bond, the formation of iron phosphate and sulfate was proposed to occur. 

Recently, the reactivity of alkylated TPPTs with air-oxidized steel was investigated in our group [25, 26]. In the absence of mechanical stress, the phosphorothionate molecules adsorbed on the substrate at low temperature (303-353 K), as described by Koyama et al. [27], The activation temperature for the thermal decomposition of TPPT molecules was found to be around 423 K. The thermal films produced at this temperature consisted of short-chain polyphosphates and oxidized sulfur species, as indicated by the XPS results. The proposed reaction mechanism started with the P=S bond scission, followed by the cleavage of the C-O or P-O bond. The released sulfur was then oxidized to form sulfates. 

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