Organophosphorus (OP) insecticides, widely used in agriculture and public health, display a very wide range of acute toxicity levels and are a potential hazard to many individuals. Metabolism and biochemical protective mechanisms were studied during the original grant period. One of the most significant observations was the presence in the brain of phosphorothionate desulfuration (activation) activity which, while very low compared to liver, correlated directly with acute toxicity level, whereas hepatic activity did not. A second important observation was that the Ca++- dependent A-esterases hydrolyze only a few oxons at low, toxicologically-relevant substrate concentrations, and this hydrolysis contributes to the low toxicity displayed by their corresponding phosphorothionates. The following hypothesis will be investigated in the renewal project: The overall toxicity level of a phosphorothionate insecticide is determined mainly by the level of brain desulfuration activity, with lesser contributions by the detoxication pathways. This hypothesis will be investigated primarily by intensive study in the rat of the monooxygenases in the brain, and the A-esterases in several tissues, primarily the liver. There will be three major specific aims: 1) To characterize the brain monooxygenases responsible for phosphorothionate desulfuration through immunological recognition, substrate specificity and kinetics of brain cytochrome P450; 2) To characterize the A-esterases responsible for oxon hydrolysis by tissue and subcellular distribution and assessment of whether the low affinity and high affinity esterases are identical; and 3) A structure-activity relationship study to characterize the structural requirements of substrates for low brain phosphorothionate activation and for high affinity oxon hydrolysis. The resultant information will be of value in the rational development of safer OP insecticides.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004394-07
Application #
3252539
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1987-08-01
Project End
1995-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
7
Fiscal Year
1993
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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