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Mechanisms of organophosphorus ester-induced delayed neurotoxicity: Type I and type II.
Annu Rev Pharmacol Toxicol 1990 Apr; 30:405-440
Organophosphorus compounds with delayed neurotoxic properties were reviewed. Type-I compounds included derivatives of phosphoric, phosphonic, phosphoramidic-acids, and phosphorofluoridates, and have a pentavalent phosphorus atom. Type-II compounds were phosphorus- acid derivatives, with a trivalent phosphorus atom. Both types exhibited: direct or indirect inhibition of esterases, latent interval between time of exposure and the onset of clinical signs, central and peripheral nervous system effects, production of uniformly characteristic neuropathologic lesions, and species specific effects. Differences were associated with: chemical structure, species selectivity, age sensitivity, length of latent period, clinical neurological signs, morphology and distribution of neuropathologic lesions, protection with phenylmethyl-sulfonyl- fluoride, inhibition of neurotoxic esterases, and effect on catecholamine secretion from bovine adrenomedullary chromaffin cells. Many cases of type-I compound organophosphorus-ester induced delayed neurotoxicity in humans have been documented. Triphenyl- phosphite, a type-II compound, was clinically used as an anticonvulsant but discontinued because it produced spinal cord lesions. The role of compounds as inhibitors of acetylcholinesterase was discussed. Neurologic symptoms of organophosphorus poisoning included progressive, stationary, and improvement phases. Prognosis and recovery depended on the severity of neurologic deficit. The author suggests that the neurotoxic mechanism of type-I compounds may be triggered by the phosphorylation of calcium-calmodulin-kinase-II. This results in enhanced calcium activated cytoskeletal protein proteolysis, which in turn impairs axonal transport by accumulation at distal axons.
NIOSH-Publication; NIOSH-Grant; Neurotoxic-effects; Nervous-system-disorders; Comparative-toxicology; Enzyme-activity; Humans; Laboratory-animals; Neurotoxicology; Organo-phosphorus-compounds
Pharmacology Duke University Department of Pharmacology Durham, N C 27710
Neurotoxic Disorders; Neurotoxic-effects
Annual Review of Pharmacology and Toxicology
Duke University, Durham, North Carolina
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