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IN VITRO EFFECTS OF CHLORPYRIFOS, PARATHION, METHYL PARATHION AND THEIR OXONS ON CARDIAC MUSCARINIC RECEPTOR BINDING IN NEONATAL AND ADULT RATS. (R825811)
Citation:
Howard, M. D. AND C. N. Pope. IN VITRO EFFECTS OF CHLORPYRIFOS, PARATHION, METHYL PARATHION AND THEIR OXONS ON CARDIAC MUSCARINIC RECEPTOR BINDING IN NEONATAL AND ADULT RATS. (R825811). TOXICOLOGY. American Chemical Society, Washington, DC, 170:1-10, (2002).
Description:
Organophosphorus insecticides elicit toxicity by inhibiting acetylcholinesterase. Young animals are generally more sensitive than adults to these toxicants. A number of studies reported that some organophosphorus agents also bind directly to muscarinic receptors, in particular the m2 subtype, in tissues from adult rats. As both the density and agonist affinity states of cardiac muscarinic receptors (primarily m2) have been reported to change in an age-related manner, we evaluated the relative in vitro sensitivity of cardiac muscarinic receptors in tissues from neonatal (7¯11 days of age) and adult (90 days of age) rats to selected organophosphorus compounds (chlorpyrifos, parathion, methyl parathion and their oxygen analogs or oxons). The effects of the cholinergic agonist carbachol (100 pM¯5 
M) or an organophosphorus toxicant (50 pM¯10 M) on muscarinic receptor binding were determined using the nonselective muscarinic ligand [3H]quinuclidinyl benzilate or the m2-preferential ligand [3H]oxotremorine-M acetate. Carbachol displaced [3H]oxotremorine labeling in adult and neonatal membranes in a relatively similar manner (IC50=7¯20 nM). The oxons all displaced [3H]oxotremorine binding in a concentration-dependent manner, with chlorpyrifos oxon being the most potent (IC50: neonates, 15 nM; adults, 7 nM) and efficacious (maximum displacement: neonates, 42%; adults, 56%). Interestingly, methyl parathion was an extremely potent displacer of [3H]oxotremorine binding in adult tissues (IC50=0.5 nM, maximum DISPLACEMENT=37%) but had no effect in neonatal tissues. The displacement of [3H]oxotremorine binding by chlorpyrifos oxon (10 M) was still apparent after washing the tissues, suggesting the oxon irreversibly blocked agonist binding to the receptor while interaction with MePS appeared reversible. As effective concentrations of the oxons were relatively similar to their anticholinesterase potencies, these findings suggest that direct interaction with cardiac muscarinic receptors by some organophosphorus agents may occur at relevant exposure levels and contribute to cardiac toxicity.
Author Keywords: Organophosphates; Cardiac; Age-related; Insecticides; Mechanism; Acetylcholinesterase inhibition