Chlorpyrifos oxon binds with high affinity to a population of muscarinic receptors in rat striatum.
Huff-RA; Knoth-Anderson-J; Abou-Donia-MB
Toxicologist 1992 Feb; 12(1):294
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.
Neurotoxic-effects; Nervous-system-disorders; Neuropathy; Laboratory-animals; Agricultural-chemicals; Organo-phosphorus-compounds; Organo-phosphorus-pesticides
Neurotoxic Disorders; Neurotoxic-effects
The Toxicologist. Society of Toxicology 31st Annual Meeting, February 23-27,1992, Seattle, Washingtion
Duke University, Durham, North Carolina