Cytochrome paraoxon

Figure 2. Chemical mechanism for the metabolism of parathion to paraoxon by the Cytochrome P-450-containing monooxygenase system (6)...

The majority of the diethyl phosphate and -nitrophenol formed in the mammalian metabolism of parathion is undoubtedly derived by the action of esterases or phosphatases ( ) on paraoxon formed from parathion in a cytochrome P-450-catalyzed reaction. However, a significant portion of the diethyl phosphate and -nitrophenol must also be the result of the attack of water on the intermediate S-oxide of parathion ( ). 

The binding of sulfur and/or an activated intermediate of the phosphorus-containing portion of the parathion molecule to the endoplasmic reticulum leads to a decrease in the amount of cytochrome P-450 detectable as its carbon monoxide complex and to a decrease in the rate of metabolism of substrates such as benz-phetamine ( 19). Neither paraoxon nor any other isolatable metabolite of parathion decreases the amount of cytochrome P-450 or inhibits the ability of microsomes to metabolize substrates such a benzphetamine (19). 

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. 

If the activity of the P450 system varies among animal species, we would expect this to be reflected in the degree of activation of a phosphorothioate insecticide such as parathion. As shown in Figure 9.2, this appears to be the case (Whitehouse and Ecobichon, 1975). The approximately 20-fold difference in paraoxon production by the tissue homogenates probably reflects a combination of cytochrome P450 monooxygenase and esterase activities. 

FIG. 1. Activation of the OP piirathioit to paraoxon by cytochromes P450 (CYPs) and detoxication of paraoxon by PONi,... 

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