Tissue-Specific Effects of Chlorpyrifos on Carboxylesterase and Cholinesterase Activity in Adult Rats: Anin Vitroandin VivoComparison

Abstract

Organophosphate (OP) pesticides can bind to carboxylesterase (CaE), which may lower the concentration of OPs at the target site enzyme, acetylcholinesterase (ChE). It is unclear from the literature whether it is the CaE's affinity for the OP and/or the number of CaE molecules which is the dominant factor in determining the protective potential of CaE. We undertook a detailed,in vitroandin vivosurvey of both CaE and ChE to ascertain ifin vitrosensitivity of CaE and ChE predicted the pattern of inhibition seen afterin vivodosing with chlorpyrifos (CPF; 80 mg/kg, p.o.) in male or female adult Long–Evans rats. For the brain, thein vitrosensitivity to CPF-oxondidpredict thein vivopatterns of inhibition:In vitro,brain ChE was approximately 25 times more sensitive to the active metabolite, CPF-oxon, than brain CaE, andin vivobrain ChE was more inhibited than brain CaE. In contrast, thein vitrosensitivity of plasma ChE and CaEdid notcorrelate well with thein vivopattern of inhibition:In vitro,plasma ChE was approximately 6.5 times less sensitive to CPF-oxon than plasma CaE, butin vivo,plasma ChE was more inhibited than CaE. In order to understand the role of CaE in protecting the brain ChE from inhibition by CPF-oxonin vitro,adult rat striatal tissue was incubated in the presence and absence of adult rat liver tissue and IC₅₀s of CPF-oxon were determined. The increase in the striatal CPF-oxon IC₅₀value noted for ChE in the presence of liver suggested that CaE was binding the CPF-oxon and limiting its access to ChE. Male liver CaE, which has the same affinity for binding CPF-oxon as female liver CaE but has twice as many binding sites, caused a greater increase in the striatal CPF-oxon IC₅₀than female liver, suggesting that the number of binding sites does play a role in the detoxification potential of a tissue. In summary, we found that (1) there are tissue and gender-related differences for basal ChE and CaE activity; (2) thein vitrosensitivity of CaE or ChE to CPF-oxon is highly tissue-specific; (3) the pattern of ChE and CaE inhibition afterin vivodosing with CPF is not necessarily predictable from thein vitroIC₅₀for these same enzymes, and (4) the number of CaE molecules may play a role in modifying the toxicity of CPF.