Chlorpyrifos metabolism

Foimaiion of in vitm blood-brain barrier (BBB) with astrocytes on "abluminar side, endothelial cells on luminal side chlorpyrifos metabolized on luminal side chlorpyrifos and its metabolites cross BBB and inhibit earbo.xylesCerase and cholinesterase in endothelial cells chlorpyrifos impairs BBB structure and integrity. Astrocytes, which are required for BBB integrity, are a potential target for chloipyrifos toxicity in this model. 

Crane AL, Klein K, Zanger UM, Olson JR (2012) Effect of CYP2B6 6 and CYP2C19 2 genotype on chlorpyrifos metabolism. Toxicology 293 115-122... 

Rawlings, N.C., S.J. Cook, and D. Waldbillig. 1998. Effects of the pesticides carbofuran, chlorpyrifos, dimethoate, lindane, triallate, trifluralin, 2,4-D, and pentachlorophenol on the metabolic endocrine and reproductive endocrine system in ewes. Jour. Toxicol. Environ. Health 54A 21-36. 

Figure 14.1 Structures of chlorpyrifos and some of its metabolites. (Modified from Barron, M.G., S.M. Plakas, and PC. Wilga. 1991. Chlorpyrifos pharmacokinetics and metabolism following intravascular and dietary administration in channel catfish. Toxicol. Appl. Pharmacol. 108 474-482.)...

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. 

Cross-tolerance between disulfoton and another organophosphate, chlorpyrifos, was observed in mice (Costa and Murphy 1983b). Because of this cross-tolerance, a benefit is derived as a result of this interaction. In the same study, propoxur-tolerant mice were tolerant to disulfoton but not vice versa. Propoxur (a carbamate) is metabolized by carboxylesterases, and these enzymes are inhibited in disulfoton-tolerant animals disulfoton-tolerant animals are more susceptible to propoxur and/or carbamate insecticides than are nonpretreated animals. In another study, disulfoton-tolerant rats were tolerant to the cholinergic effects of octamethyl pyrophosphoramide (OMPA) but not parathion (McPhillips 1969a, 1969b). The authors were unable to explain why the insecticides OMPA and parathion caused different effects. 

Dai D, Tang J, Rose R, Hodgson E, fiienstock RJ, Mohrenweiser HW, Coldstein JA (2001) Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther 299 825-831... 

The chlorpyrifos example described in Appendix B illustrates another caveat related to biomarkers that are urinary metabolites. A metabolite can sometimes appear in urine not only as a result of parent-chemical uptake and metabolism but also as a result of uptake of the metabolite from environmental media (Tu et al. 2005 Wilson et al. 2003). Thus, the biomarker for chlorpyrifos, 3,5,6-trichloro-2-pyridinol (TCP), occurs in a wide variety of environmental media, and the concentration in foods surpasses that of the parent chemical (Morgan et al. 2005). If the intake of the metabolite from environmental sources is substantial in comparison with that of the parent chemical, as in the case of chlorpyrifos and TCP, the extrapolation of urinary biomarker concentration to parent-chemical exposure dose is uncertain. 

Kersting K, van den Brink PJ. 1997. Effects of the insecticide Dursban 4E (active ingredient chlorpyrifos) in outdoor experimental ditches III Responses of ecosystem metabolism. Environ Toxicol Chem 16 251-259. 

A recent publication on PBTK/TD modeling to determine dosimetry and cholinesterase inhibition for a chemical mixture of 2 organophosphorus insecticides, chlo-rpyrifos and diazinon (Timchalk and Poet 2008), deserves some special discussion here. Based on the individual PBTK/TD models developed earlier by the same laboratory, Timchalk and Poet (2008) reported their development of a binary interaction PBTK/TD model for chlorpyrifos and diazinon. In their development of the model, Timchalk and Poet (2008) took into consideration a number of important metabolic steps (CYP450 mediated activation and detoxification of a number of esterases—B-... 

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