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ToxSci Advance Access originally published online on October 3, 2006
Toxicological Sciences 2007 95(1):147-155; doi:10.1093/toxsci/kfl123
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Age-Related Brain Cholinesterase Inhibition Kinetics following In Vitro Incubation with Chlorpyrifos-Oxon and Diazinon-Oxon

Ahmed A. Kousba*,1, Torka S. Poet{dagger} and Charles Timchalk{dagger}

* Department of Pharmaceutical Property Assessments, TargeGen Inc., San Diego, California 92121 {dagger} Battelle, Pacific Northwest Division, Richland, Washington 99352

1 To whom correspondence should be addressed at Department of Pharmaceutical Property Assessments, TargeGen, Inc., 9380 Judicial Drive, San Diego, CA 92121. Fax: (858) 678-0762. E-mail: akousba{at}targegen.com.

Received September 26, 2006; accepted September 27, 2006


  Abstract

Chlorpyrifos and diazinon are two commonly used organophosphorus insecticides (OPs), and their primary mechanism of action involves the inhibition of acetylcholinesterase by their metabolites chlorpyrifos-oxon (CPO) and diazinon-oxon (DZO), respectively. The study objectives were to assess the in vitro age-related inhibition kinetics of neonatal rat brain cholinesterase (ChE) for CPO and DZO by estimating the bimolecular inhibitory rate constant (ki) values. Brain ChE inhibition and ki values following CPO and DZO incubation with neonatal Sprague-Dawley rat brain homogenates were determined at postnatal day (PND) 5, 12, and 17 and compared with the corresponding inhibition and ki values obtained in the adult rat. A modified Ellman method was utilized for measuring the ChE activity. CPO caused a greater ChE inhibition than DZO as evidenced from the estimated ki values of both compounds. Neonatal brain ChE inhibition kinetics exhibited a marked age-related sensitivity to CPO, with the order of ChE inhibition being PND 5 > PND 7 > PND 17 with ki values of 0.95, 0.50, and 0.22nM–1hr–1, respectively. In contrast, DZO ChE inhibition was not age related in the neonatal brain, and the estimated ki value at all PND ages was 0.02nM–1hr–1. These results demonstrated an age- and OP-selective inhibition of rat brain ChE, which may be critically important in understanding the potential sensitivity of juveniles to specific OPs exposures.

Key Words: cholinesterase; organophosphate insecticide; chlorpyrifos-oxon; diazinon-oxon.


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