Chlorpyrifos-oxon activation

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... 

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. 

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). 

FIG. 2, Schematic illustrating the interaction of acetj Icholine (I), the carbamate carbaryl (II), and the organophosphate ehiorpynfos-oxon (IJI) with the active site of acetylcholinesterase (ACbE). The general rate of bound AChE hydrolysis is ACh > > carbaryl > chlorpyrifos-oxon. 

Pond, A. L.. Coyne, C. R. Chambers, H. W., and Chambers, J. E. (1996). Identification and isolation of two rat serum proteins with A-esterasc activity toward paraoxon and chlorpyrifos-oxon. Biociiem. Pharmacol 52, 363-369. 

Bomser, J.. and Casida, J. E, (2000). Activation of extracellular signal-regulated kinatses (ERK 44/42) by chlorpyrifos oxon in Chinese hamster ovary cells. J. Biochem. Mol. Toxicol. 14, 346-353. 

An additional scries of experiments was carried out in mice because much less purified enzyme is required for injection and this species was deemed to be ideal for studies involving genetically modified animals with altered PONl levels. An initial experiment followed the same protocol previously utilized in rats and provided evidence that iv administration of pure rabbit PONl increased scrum chiorpyrifos-oxon activity 30- to 40-fold and protected animals from AChE inhibition by dermally applied chlorpyrifos-oxon (Li et al., 1993). As with iv injection of rabbit PONl, the increased serum PONl activity was short lasting investigating other routes of admini.stration for PONL Administration of PONl by the iv + ip route increased plasma enzyme activity tow ard chlorpyrifos-oxon 35-fold and extended the half-life to 30 hr. An even longer half-life, albeit with lower peak activity levels, was found when PON was given by the iv + im route (Li el al, 1993). 

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