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Chlorpyrifos oxon binds with high affinity to a population of muscarinic receptors in rat striatum.

Authors
Huff-RA; Knoth-Anderson-J; Abou-Donia-MB
Source
Toxicologist 1992 Feb; 12(1):294
NIOSHTIC No.
20037091
Abstract
The deleterious effects of organophosphorus compounds (OP's) are most often ascribed to inhibition of acetylcholinesterase (AChE). Recently. however, interest has arisen in the possibility that direct interactions of OP's with receptors may interfere with normal cellular processes. Using striatal membrane preparations from male Sprague-Dawley rats, we have demonstrated that the active metabolite of chlorpyrifos (O,O-diethyl 0-3,5, 6-trichloro-2-pyridinyl phosphorothioate), the oxon, binds with high affinity to a population of muscarinic receptors labelled with [3H]cis-methyldioxolane (CD). In competition experiments, chlorpyrifos oxon inhibited up to 70 percent of [3H]CD binding with an IC50 of approximately 26 nM. The affinity of the parent compound was three orders of magnitude less. Neither compound was effective in displacing [3H]quinuclidinyl benzilate (QNB) used to label the entire muscarinic receptor population. [3H]CD sites represent only 12 percent of the [3H]QNB sites. Scatchard analysis indicates that the decrease in [3H]CD binding can be attributed to a change in affinity. The binding of the oxon to [3H]CD sites occurs at concentrations which cause minimal inhibition of AChE activity. Just as for the binding data, the parent compound is approximately three orders of magnitude less effective in inhibiting AChE. The ability of chlorpyrifos oxon to bind with high affinity to a subset of muscarinic receptors may lead to post-receptor events in the absence of severe AChE inhibition. Such subsequent alterations in cellular signal transduction following chlorpyrifos oxon treatment will be investigated.
Keywords
Neurotoxic-effects; Nervous-system-disorders; Neuropathy; Laboratory-animals; Agricultural-chemicals; Organo-phosphorus-compounds; Organo-phosphorus-pesticides
Publication Date
19920201
Document Type
Abstract
Funding Amount
1567389
Funding Type
Grant
Fiscal Year
1992
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-00823
Issue of Publication
1
ISSN
0731-9193
Priority Area
Neurotoxic Disorders; Neurotoxic-effects
Source Name
The Toxicologist. Society of Toxicology 31st Annual Meeting, February 23-27,1992, Seattle, Washingtion
State
NC
Performing Organization
Duke University, Durham, North Carolina
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