Paraoxon parathion desulfuration

Figure 9.2 Initial rates of parathion desulfuration by hepatic microsomes of representative males and females of different mammalian species. Activity was determined at 37°C using an initial substrate concentration of 2 x 10 1 M parathion. The bars represent the mean activities (nmol of paraoxon/min/mg protein) of the number of animals shown. The lines represent the standard deviations of the mean values. (From Whitehouse, L.W. and Ecobichon, D.J., Pestic. Biochem. Physiol., 5, 314,1975. With permission.)...

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. 

In thio compounds, desulfuration results from substitution of sulfur by oxygen (e.g parathion). This example again illustrates that biotransformation is not always to be equated with bioinactivation. Thus, paraoxon (E600) formed in the organism from parathion (E605) is the actual active agent (p. 102). 

Desulfuration. Replacement of sulfur by oxygen is known to occur in a number of cases, and the oxygenation of the insecticide parathion to give the more toxic paraoxon is a good example of this (Fig. 4.25). This reaction is also important for other phosphorothionate insecticides. 

Desulfuration is the term given to removal of sulfur from a molecule. One of the most common desulfuration reactions occurs with sulfur bonded to phosphorus. A common desulfuration reaction is the enzyme-mediated conversion of parathion to paraoxon (see discussion of organophosphate insecticides in Section 18.7) ... 

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. 

Even a rather simple insecticide such as methyl parathion is transformed by insects in a complex manner. The parent insecticide is activated to methyl paraoxon, which is a more potent inhibitor of the target, acetylcholinesterase in the nerve (Figure 1). This activating desulfuration is catalyzed by monooxygenases. Both the parent and the oxon are subject to detoxication by monooxygenase and glutathione transferase, while the oxon is also more labile to hydrolysis. 

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]. 

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. 

---