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ToxSci Advance Access published online on October 3, 2006
Toxicological Sciences, 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
Received July 31, 2006
Accepted September 22, 2006

Neurotoxicology

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

A. A. Kousba 1 *, T. S. Poet 2, and C. Timchalk 2

1 Current address: TargeGen Inc., 9380 Judicial drive, San Diego, CA, 92121, USA
2 Battelle, Pacific Northwest Division, PO Box 999, Richland, WA 99352, USA

* To whom correspondence should be addressed.
A. A. Kousba, E-mail: akousba{at}targegen.com


  Abstract

Chlorpyrifos and diazinon are two commonly used organophosphorus insecticides (OPs), and their primary mechanism of action involves the inhibition of acetylcholinesterase (AChE) 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 post natal 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. Chlorpyrifos-oxon 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 was PND-5 > PND-7 > PND-17 with ki values of 0.95, 0.50 and 0.22 nM-1hr-1, respectively. In contrast, DZO ChE inhibition was not age-related in neonatal brain, and the estimated ki value at all PND ages was 0.02 nM-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.

Keywords: Cholinesterase; organophosphate insecticide; chlorpyrifos oxon; diazinon-oxon.
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