Parathion oxidative desulfuration

Insecticides of the phosphoric acid triester class include paraoxon (9.49) and dichlorvos (9.50). The phosphorothioate derivative parathion is a relatively non-toxic insecticide that undergoes monooxygenase-catalyzed oxidative desulfuration to paraoxon [105] (see also Chapt. 7 in [59] see Sect. 9.3.6). Paraoxon itself, like its congeners and the P-halide nerve gases, is highly toxic through its potent inactivation of acetylcholinesterase [69]. 

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. 

Epoxidation and hydroxylation A-Dealkylation O-Dealkylation -Dealkylation -Oxidation A-Oxidation P-Oxidation Desulfuration Dehalogenation Nitro reduction Azo reduction Cytochrome P450 (CYP) Aflatoxin, aldrin, benzo[a]pyrene, bromobenzene, naphthalene Ethylmorphine, atrazine, dimethylnitrocarbamate, dimethylaniline p-Nitroanisole, chlorfenvinphos, codeine Methylmercaptan Thiobenzamide, phorate, endosulfan, methiocarb, chlorpromazine 2-Acetylaminofluorene Diethylphenylphosphine Parathion, fonofos, carbon disulfide CCLt, CllCb Nitrobenzene O-Aminoazotoluene Flavin-Containing Monooxygenase (FMO)... 

Organophosphate insecticides with the P=S group are oxidatively desulfurated by cytochrome P450 monooxygenases of insects to their corresponding P=0 analogs. This reaction results in activation (increased toxicity), because the product, P=0, binds more tightly to the acetylcholinesterase than the parent compound and, thus, to more potent acetylcholinesterase inhibitors. For example, parathion is oxidatively desulfurated to paraoxon. 

Parathion or 0,0-diethyl 0-(4-nitrophenyl) phosphorothioate Organophosphate Cholinesterase inhibitor, nonsystemic contact, stomach and respiratory action, activated by oxidative desulfuration Control of sucking and chewing insects and mites in field crops, fruits, and vegetables 11-22... 

Such a pathway does, however, exist in insects. In the latter species, parathion and malathion act as prodrugs. They are metabolized by oxidative desulfurization to give the active anticholinesterases which irreversibly bind to the insects acetylcholinesterase enzymes and lead to death. In mammals, the same compounds are metabolized in a different way to give inactive compounds which are then excreted (Fig. 11.59). 

Kamataki et al. [10] have shown that a phenobarbital-inducible form of P450 (probably P450 2B1) catalyzed the oxidative activation and detoxication of parathion (reaction VI in Figure 1). The products formed were identified both in vitro and in vivo and comprise 60-70% paraoxon, 20-30% diethyl phosphoro-thionate and 5-10% diethyl phosphate with some reactive sulfur. Among other OPC that follow the proposed mechanism of oxidative desulfuration were methyl parathion and chlorpyriphos [11]. 

OP insecticides having phosphonate and carbamate structure that contain thioether bonds are good substrates for FMO. These enzymes participate in oxidative desulfuration (P=S P=0) of OPC such as fonofos and phenylfonofos [22, 23]. It has been shown that FMO requires P-C bond in OPC since it acts directly on phosphorus atom, while oxidative desulfuration with P450 occurs on sulfur that is bound to phosphorus (P=S). For that reason parathion and some phosphorodithionates are not FMO substrates. Compounds of trivalent phospho-... 

Kyle PB, Smith SV, Baker RC, Kramer RE (2013) Mass spectrometric detection of CYP450 adducts following oxidative desulfuration of methyl parathion. J Appl Toxieol 33 644-651... 

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. 

Some of these irreversible AChEI insecticides have a sulfur atom bonded to the phosphorus atom ith a coordinate-covalent bond. These compounds exhibit little AChEI activity, but they are rapidly bioactivated via desulfurization by microsomal oxidation in insects to afford the corresponding oxo derivatives (phosphate esters), hich are quite potent. A good example of this bioactivation phenomenon is illustrated by the commercially available insecticide parathion and its bioactivation to a toxic metabolite paraoxon. 

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