Paraoxon binding

Methyl parathion can enter your body if you eat food or drink water containing it if you swim, bathe, or shower in contaminated water if you touch recently sprayed plants or soil if you touch contaminated soil near hazardous waste sites or if you breathe air that contains methyl parathion, such as near factories or recently sprayed farm fields (or in recent accounts of the illegal use of methyl parathion, if you breathe air or touch contaminated surfaces inside homes where methyl parathion has been used to kill insects). By any means of exposure, methyl parathion goes into your body quickly and gets into your blood. From your bloodstream, methyl parathion goes to your liver, brain, and other organs. Your liver changes some of methyl parathion to a more harmful chemical called methyl paraoxon. Both methyl parathion and methyl paraoxon can bind to enzymes of your nerves within minutes or hours. Your liver breaks down methyl parathion and methyl paraoxon into less harmful substances. These less harmful substances leave your body in urine within hours or days. For more information, see Chapter 3. 

Methyl paraoxon may also be made unavailable by binding to noncritical tissue and plasma constituents (Benke and Murphy 1975), including cholinesterase (Parkinson 1996). In addition, the parent compound is bound to albumin, in serum, as discussed previously in Section 3.4.2.4, but this binding does not appear to limit the availability of methyl parathion to the tissues, indicating that it is reversible. Tissue binding appears to be more important than serum binding (Braeckman et al. 1980, 1983). 

Data from a single study in dogs suggest that hepatic first-pass metabolism may limit systemic availability of the parent compound following oral exposure (Braeckman et al. 1983). Placental transfer of methyl parathion was demonstrated in pregnant rats 1-3 days before parturition. Thirty minutes after administration, both methyl parathion and methyl paraoxon were found in fetal brain, liver, and muscle methyl parathion, but not methyl paraoxon, was detected in placenta and maternal liver (Ackermann and Engst 1970). Methyl parathion binds reversibly to serum albumin, but is readily distributed to the tissues (Braeckman et al. 1980, 1983). 

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). 

The methanolyses of several phosphate/phosphonate esters and their thio analogues [e.g. 0,0-diethyl 0-(4-nitrophenyl) phosphate, paraoxon (101 X = O, Z = 4-N02), 0,0-diethyl S- S-dichlorophenyl) phosphorothioate, (102 R = OEt), and 0-ethyl S-OA-dichlorophenyl) methylphosphonothioate (102 R = Me)] catalysed by methoxide and the complex of Zn2+ (MeO-) with 1,5,9-triazacyclododecane (79 M = Zn) were studied in methanol at 25 °C. The reaction of methoxide and (79 M = Zn) with the entire series of esters appears to adhere to a common mechanism that involves pre-equilibrium binding of the substrate, followed by intramolecular attack of the coordinated methoxide concerted with OAr or SAr leaving group departure.79... 

An example of irreversible binding is that of paraoxon, which can be viewed as an organophosphate compound containing a phosphorylating group (P) and a leaving group (L), as shown below ... 

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. 

As outlined in Figure 3, the hydrolysis of paraoxon by human serum A-esterase(s) is very similar to the phosphorylation of B-esterases, such as acetylcholinesterase, by paraoxon. Both reactions involve an initial binding of paraoxon to the enzyme, followed by a rapid conformational change that produces diethyl phosphate and p-nitrophenol from paraoxon. p-Nitrophenol is quickly released from the enzyme, leaving diethyl phosphate covalently bound to enzyme. At this point, A-esterase quickly releases diethyl phosphate as a result of interacting with a water molecule. However, B-esterases, such as acetylcholinesterase, retain the diethyl phosphate for a much longer period of time, thereby resulting in inhibition of the enzyme. 

Parathion binds tightly to soil particles and has little or no potential for groundwater contamination. Residues of parathion may persist for days or weeks. Parathion readily undergoes photodegradation and sunlight can convert parathion into paraoxon. The breakdown of parathion in soil or water increases with alkalinity. Parathion residues on crops typically decay with a half-life of 1 day. 

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