Phosphorothionates enzyme activation

Inhibition of the cholinesterase enzymes depends on blockade of the active site of the enzyme, specifically the site that binds the ester portion of acetylcholine (Fig. 7.48). The organophosphorus compound is thus a pseudosubstrate. However, in the case of some compounds such as the phosphorothionates (parathion and malathion, for example), metabolism is necessary to produce the inhibitor. 

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. 

Acute toxicity levels are influenced by the hepatic cytochrome P450 enzymes that activate phosphorothionate... 

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. 

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