Phosphorothionate insecticides must be metabolized by cytochrome P-450-dependent monooxygenases into their oxons to be potent anticholoinesterases. Because the oxon can be readily detoxified, and because it can inhibit a variety of non-target esterases as well as bind non-specifically to proteins, it is rather unlikely that much of the hepatically-formed oxon could be available to inhibit brain acetylcholinesterase (AChE) to cause toxicity. The project will test the following hypothesis: Because of the efficient protective mechanisms in the liver and blood which prevent hepatically-generated oxon from reaching the target AChE in the brain, the monooxygenase-mediated activation of phosphorothionate insecticides in the brain contributes significantly to the development of acute symptomology. The project will investigate how important the phosphorothionate activiation in the brain is to the poisoning phenomenon by 1) characterizing this activation activity and by 2) quantitating the possible protective mechanisms existing in liver and blood which could provent hepatically-generated oxon from reaching target AChE in the brain. The project will study: phosphoroothionate activation and detoxication, and other monoocxygenase activites in the brain, compared to similar activity profiles from the liver; oxon hydrolysis; in vitro sensitivity of target AChE and protective liver and blood esterases to oxon inhibition, and the recovery of esterase activity; lifetime of active anticholinesterase in the blood; non-specific oxon binding to and release from proteins; and correlation of lethality with brain AChE inhibition. Metabolism will be studied radiometrically, or spectrophotometrically by assay o the anticholoinesterase activity of the oxon and the absorbance of the leaving group. Oxon concentration will be assessed by the quantitation of anticholinesterase activity; esterases will be monitored spectrophotometrically. Surgical techniques will isolate brain from liver to monitor the significance of each metabolism. The project is expected to define the importance of each metabolic activity and protective capacity in the overall toxic response of an organism to a phosphorothionate. The resultant information, by contributing to a better understanding of the factors influencing acute toxicity, will allow better predictions of the therapy required for a victim of an accidental poisoning by a phosphorothionate insecticide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004394-03
Application #
3252536
Study Section
Toxicology Study Section (TOX)
Project Start
1987-08-01
Project End
1990-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Mississippi State University
Department
Type
Schools of Arts and Sciences
DUNS #
075461814
City
Mississippi State
State
MS
Country
United States
Zip Code
39762
Chambers, Janice E (2008) PON1 multitasks to protect health. Proc Natl Acad Sci U S A 105:12639-40
Tang, Jun; Carr, Russell L; Chambers, Janice E (2003) The effects of repeated oral exposures to methyl parathion on rat brain cholinesterase and muscarinic receptors during postnatal development. Toxicol Sci 76:400-6
Tang, J; Carr, R L; Chambers, J E (1999) Changes in rat brain cholinesterase activity and muscarinic receptor density during and after repeated oral exposure to chlorpyrifos in early postnatal development. Toxicol Sci 51:265-72
Tang, J; Chambers, J E (1999) Detoxication of paraoxon by rat liver homogenate and serum carboxylesterases and A-esterases. J Biochem Mol Toxicol 13:261-8
Crittenden, P L; Carr, R; Pruett, S B (1998) Immunotoxicological assessment of methyl parathion in female B6C3F1 mice. J Toxicol Environ Health A 54:1-20
Pond, A L; Chambers, H W; Coyne, C P et al. (1998) Purification of two rat hepatic proteins with A-esterase activity toward chlorpyrifos-oxon and paraoxon. J Pharmacol Exp Ther 286:1404-11
Atterberry, T T; Burnett, W T; Chambers, J E (1997) Age-related differences in parathion and chlorpyrifos toxicity in male rats: target and nontarget esterase sensitivity and cytochrome P450-mediated metabolism. Toxicol Appl Pharmacol 147:411-8
Carr, R L; Chambers, J E (1996) Kinetic analysis of the in vitro inhibition, aging, and reactivation of brain acetylcholinesterase from rat and channel catfish by paraoxon and chlorpyrifos-oxon. Toxicol Appl Pharmacol 139:365-73
Pond, A L; Coyne, C P; Chambers, H W et al. (1996) Identification and isolation of two rat serum proteins with A-esterase activity toward paraoxon and chlorpyrifos-oxon. Biochem Pharmacol 52:363-9
Watson, A M; Chambers, J E (1996) The effect of high and low dosages of paraoxon in beta-naphthoflavone-treated rats. J Biochem Toxicol 11:263-8

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