Chlorpyrifos oxon

There are marked species differences in A-esterase activity. Birds have very low, often undetectable, levels of activity in plasma toward paraoxon, diazoxon, pirimi-phos-methyl oxon, and chlorpyrifos oxon (Brealey et al. 1980, Mackness et al. 1987, Walker et al. 1991 Figure 2.10). Mammals have much higher plasma A-esterase activities to all of these substrates. The toxicological implications of this are discussed in Chapter 10. Some species of insects have no measurable A-esterase activity, even in strains that have resistance to OPs (Mackness et al. 1982, Walker 1994). These include the peach potato aphid (Myzus persicae Devonshire 1991) and the... 

Fish rapidly absorb, metabolize, and excrete chlorpyrifos from the diet (Barron etal. 1991). The mechanism of action of chlorpyrifos occurs via phosphorylation of the active site of acetylcholinesterase after initial formation of chlorpyrifos oxon by oxidative desulfuration. In studies with channel catfish (Ictalurus punctatus), the oral bioavailability of chlorpyrifos was 41%, substantially higher than in mammals. Catfish muscle contained less than 5% of the oral dose with an... 

Sultatos, L.G. and S.D. Murphy. 1983. Hepatic microsomal detoxification of the organophosphates paraoxon and chlorpyrifos oxon in the mouse. Drug Metabol. Dispos. 11 232-238. 

A. L. Pond, C. P. Coyne, H. W. Chambers, J. E. Chambers, Identification and Isolation of Two Rat Serum Proteins with A-Esterase Activity toward Paraoxon and Chlorpyrifos-Oxon , Biochem. Pharmacol. 1996, 52, 363-369. 

Qilorpyrifos reacted with fi ee chlorine to form chlorpyrifos oxon, which is more toxic than the parent compound. Both compounds further hydrolyze to a more stable product, 3,5,6-trichloro-2-pyridinol [110]. 

Grigoryan, H., Schopfer, L.M., Thompson, C.M., Terry, A.V., Masson, P., Lockridge, O. (2008). Mass spectrometry identifies covalent binding of soman, sarin, chlorpyrifos oxon, diisopropyl fluorophosphate, and FP-biotin to tyrosines on tubulin a potential mechanism of long term toxicity by organophos-phoms agents. Chem. Biol. Interact. April 22. (Epub ahead of print)... 

H-Chlorpyrifos oxon binds covalently to rat heart M2 musearinic receptors (Bomser and Casida, 2001). The site of attachment has not been identified. When guinea pigs were treated with chlorpyrifos, diazinon, or parathion at doses too low to inhibit acetylcholinesterase activity, the M2 muscarinic receptors lost their abihty to inhibit acetylcholine release from parasympathetic nerves, causing bronchocon-striction (Lein and Fryer, 2005). 

In a 1963 Pedler lecture, Sanger reported that H-DFP makes a covalent bond with tyrosine in the sequence Arg-TjrThrLys from human and rabbit albumin (Sanger, 1963). Mass spectrometry of human albumin treated with soman, chlorpyrifos oxon, FP-biotin, diehlorvos, and DFP confirmed OP modification on Tyr 411 in peptide LVRY TKKVPQVSTPTL (Li et al, 2007, 2008a), where the underline shows Sanger s sequence and the indieates the labeled tyrosine. 

During years of mass spectrometry analysis, we had consistently identified OP-labeled tubulin in mouse brain. Therefore, we studied pure bovine tubulin (Cytoskeleton, Inc.) by treating it with soman, sarin, FP-biotin, DFP, chlorpyrifos oxon, and dichlorvos. We isolated the OP-labeled tryptic peptides and analyzed them by fragmentation in the QTRAP 2000 and QTRAP 4000 mass spectrometers. We identified five OP-labeled peptides in tubulin (Grigoryan et al, 2008). In every peptide, the OP was covalently attached to tyrosine (Table 56.1). 

Similar mass spectrometry experiments with pure human and mouse transferrin (Li et al., 2008c), and with human kinesin showed that the OP label was consistently on tyrosine (Table 56.1). Studies with human plasma identified OP labeling on tyrosine in apolipoprotein and alpha-2-glyco-protein. Aggressive treatment of hiunan albumin with FP-biotin and chlorpyrifos oxon led to identification of seven OP-labeled tyrosines (Ding et al, 2008). Finally, we found that synthetic peptides made a covalent bond with DFP, chlorpyrifos oxon, and dichlorvos (Table 56.1). Mass spectrometry conclusively proved that the OP was attached to tyrosine. 

Bomser, J.A., Casida, J.E. (2001). Diethylphosphorylation of rat cardiac M2 muscarinic receptor by chlorpyrifos oxon in vitro. Toxicol. Lett. 119 21-6. 

Gearhart, D.A., Sickles, D.W., Buccafusco, J.J., Prendergast, M.A., Terry, A.V., Jr. (2007). Chlorpyrifos, chlorpyrifos-oxon, and diisopropylfluorophosphate inhibit kinesin-dependent microtubule motility. Toxicol. Appl. Pharmacol. 218 20-9. 

Kropp, T.J., Richardson, R.J. (2003). Relative inhibitory potencies of chlorpyrifos oxon, chlorpyrifos methyl oxon, and mipafox for acetylcholinesterase versus neuropathy target esterase. J. Toxicol. Environ. Health Part A 66 1145-57. 

Cole, T.B., Walter, B.J., Shih, D.M., Tward, A.D., Lusis, A.J., Timchalk, C., Richter, R.J., Costa, L.G., Furlong, C.E. (2005). Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PONl) Q192R polymorphism. Pharmacogenet. Genom. 15 589-98. 

Costa, L.G., McDonald, B.E., Murphy, S.D., Omerm, G.S., Richter, R.J., Motulsky, A.G., Furlong, C.E. (1990). Serum paraoxonase and its influence on paraoxon and chlorpyrifos-oxon toxicity in rats. Toxicol. Appl. Pharmacol. 103 66-76. Cowan, F.M., Broomfield, C.A., Stojiljkovic, M.P., Smith, W.J. (2004). A review of multi-threat medical countermeasures against chemical warfare and terrorism. Mil. Med. 169 850-5. 

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