Paraoxon neurotoxicity

Henderson, J.D., R.J. Higgins, J.C. Dacre, et al. 1992. Neurotoxicity of acute and repeated treatments of tabun, paraoxon, diisopropyl fluorophosphate and isofenphos to the hen. Toxicology 72 117-129. 

FIGURE 69.3. In vitro protection of AChE from inhibition hy paraoxon or DFP by enzymatic hioscavengers (OPH or OPAA) and 2-PAM. The P50 value is the ratio at which 50% of a fixed concentration of AChE is protected from neurotoxic poisoning. From left to right, the kinetic curves are (1) OPH and paraoxon (2) OPH and DFP (3) OPAA and DFP (4) 2-PAM and paraoxon (5) 2-PAM and DFP (6) OPAA and paraoxon. 

The esterase got the names neurotoxic esterase or neuropathy target esterase, and the ester phenyl valerate (PV) was found to be a good substrate for this esterase. However, PV is also hydrolyzed by other esterases because paraoxon, which does not give symptoms of delayed neurotoxicity, inhibited the PV activity as much as 80%. The NTE is defined as the hydrolytic activity against PV that is not inhibited by paraoxon but by mipafox. About 3% of the activity is not inhibited by mipafox plus paraoxon. Thus, the part of PV activity due to neurotoxic esterase should be 17%. 

The assay of NTE uses hen brain tissue, which contains substantial esterase activity with phenyl valerate substrate. It should include the use of comparative compounds that are neurotoxic (e.g., mipafox) and non-neurotoxic (e.g., paraoxon) as inhibitors of the enzyme for comparative purposes (Johnson 1977 Johnson and Riehardson 1983 Correll and Ehrich 1991 Richardson et al. 1993 Seifert and Wilson 1994). 

Sanche/.-Siinied, K, Canadas, E, Elores, P., Lopcz-Grancha, M and Cardona, D. (2004). Long-term functional neurotoxicity of paraoxon and chlorpyrifos Behavioural and pharmacological evidence. Neuminxicol. Teralol. 26, 30. )-3l7. 

In human populations, serum PON1 exhibits a substrate-dependent polymorphism to the neurotoxic effects of organophosphates in those susceptible individuals that are deficient in PON1 (i.e., PM phenotype) (55). The PON1 catalyzes the hydrolysis of paraoxon, chlorpyrifos (Dursban), and other orgahophosphates. 

The capability of the OPH fabric to hydrolyze a variety of organophosphate neurotoxins has been clearly demonstrated. These towelettes hydrolyze practical quantities of neurotoxic pesticides and chemical nerve agents. An OPH towelette that is 10 cm X 10 cm and four layers thick would yield a total of 400 cm. Data from Table II shows that crude OPH coupled to mono-gly cotton can hydrolyze 0.12 mg paraoxon/min/cm of fabric. Therefore, a decontamination towelette, of the above dimensions, could hydrolyze 48 mg of paraoxon per minute. Even modest optimization of the towelette would likely produce a fabric that can decontaminate gram quantities of agent in just a few minutes. Based on absorbency data for cotton (not shown), a flannel towelette of the above dimensions could absorb up to 35 milliliters of fluid. 

Johnson (1969b, 1970) assumed that phosphorylable sites would be serine-containing proteins. Several car-boxylesters were tested to find a selective substrate able to interact in the same site (able to reduce the speed of [ P]DFP labeling on the mipafox binding fraction). Phenyl-phenyl acetate was selected as that substrate. In other studies, PV was observed to be more selective and has been used for decades for testing the target site, the neurotoxic esterase, and was later called the NTE. NTE has been monitored as the PVase activity resistant to 40 pM paraoxon (20 min) ("B" activity) and sensitive to 40 pM paraoxon plus 60-150 pM mipafox ("C" activity), with NTE as the difference between the activity in condition B and condition C. 

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