Potentiation and neurotoxicity induced by certain organophosphates

Casida, John E.; Baron, Ronald L.; Etō, Morifusa; Engel, Judith L.

doi:10.1016/0006-2952(63)90011-x

Cited by 107 publications

(40 citation statements)

References 11 publications

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“…In contrast, the long lasting nature of the DEF action suggested a relatively slow removal from the body. The carboxylesterase-inhibitory action of DEF reported by Casida et al (1963) for mice lasted 3 to 5 days, a similar value to the 2 to 3 day duration of the rat hypothermia seen in the present study.…”

Section: Discussionsupporting

confidence: 90%

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SELECTIVE INHIBITION OF THERMOGENESIS BY TRIBUTYL S,S,S,‐PHOSPHOROTRITHIOATE (DEF)

Ray

1980

British J Pharmacology

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1 Rats and mice given tributyl S,S,S,-phosphorotrithioate (DEF) showed large dose-related falls in body temperature which lasted from several hours to several days at environmental temperatures below thermoneutrality (30 to 31°C).2 DEF produced only mild sedation and a remarkable degree of motor control was retained even when body temperatures fell below 30°C. At the dose producing maximal hypothermia only 2% of rats died within the first 24 h, although prolonged hypothermia was usually lethal. 3 Hypothermia was associated with a complete block of cold-induced thermogenesis, with relatively little effect on basal metabolism at thermoneutrality. 4 Heat conservation mechanisms (peripheral vasoconstriction and piloerection) appeared to be unaffected by DEF and retained their usual temperature thresholds. 5 Adrenal catecholamine secretion in response to handling or acute cold exposure was normal in DEF-treated rats but the fall in body temperature could be markedly reduced by large intraperitoneal injections of noradrenaline, although not atropine. The increase in oxygen consumption produced by injected catecholamines was also unaffected by DEF treatment. 6 It is concluded that the block of cold-induced thermogenesis probably results from a lack of catecholamine release at the tissue level. That this is likely to be mediated at a peripheral site is suggested by the lack of effect of intracerebroventricular DEF.

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Section: Discussionsupporting

confidence: 90%

“…It is a poor inhibitor of acetylcholinesterase, but has found biochemical application as a general carboxyesterase inhibitor (Casida, Baron, Eto & Engel, 1963;Silver & Murphy, 1978) at 2 to 20 mg/kg. Symptoms of acetylcholinesterase inhibition are not seen below 400 mg/kg.…”

Section: Introductionmentioning

confidence: 99%

SELECTIVE INHIBITION OF THERMOGENESIS BY TRIBUTYL S,S,S,‐PHOSPHOROTRITHIOATE (DEF)

Ray

1980

British J Pharmacology

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“…9). Other OP delayed neurotoxicants are the insecticide mipafox, which is no longer used (4,5), and the cotton defoliant tribufos (10). Their structures are given in Fig.…”

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confidence: 99%

Evidence that mouse brain neuropathy target esterase is a lysophospholipase

Quistad

Barlow²,

Winrow³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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122

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Neuropathy target esterase (NTE) is inhibited by several organophosphorus (OP) pesticides, chemical warfare agents, lubricants, and plasticizers, leading to OP-induced delayed neuropathy in people (>30,000 cases of human paralysis) and hens (the best animal model for this demyelinating disease). The active site region of NTE as a recombinant protein preferentially hydrolyzes lysolecithin, suggesting that this enzyme may be a type of lysophospholipase (LysoPLA) with lysolecithin as its physiological substrate. This hypothesis is tested here in mouse brain by replacing the phenyl valerate substrate of the standard NTE assay with lysolecithin for an ''NTE-LysoPLA'' assay with four important findings. First, NTE-LysoPLA activity, as the NTE activity, is 41-45% lower in Nte-haploinsufficient transgenic mice than in their wild-type littermates. Second, the potency of six delayed neurotoxicants or toxicants as in vitro inhibitors varies from IC 50 0.02 to 13,000 nM and is essentially the same for NTE-LysoPLA and NTE (r 2 ‫؍‬ 0.98). Third, the same six delayed toxicants administered i.p. to mice at multiple doses inhibit brain NTE-LysoPLA and NTE to the same extent (r 2 ‫؍‬ 0.90). Finally, their in vivo inhibition of brain NTELysoPLA generally correlates with delayed toxicity. Therefore, OP-induced delayed toxicity in mice, and possibly the hyperactivity associated with NTE deficiency, may be due to NTE-LysoPLA inhibition, leading to localized accumulation of lysolecithin, a known demyelinating agent and receptor-mediated signal transducer. This mouse model has some features in common with OP-induced delayed neuropathy in hens and people but differs in the neuropathological signs and apparently the requirement for NTE aging.

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“…From the initial reports on adulterated alcoholic beverages showing tri-o-cresyl phosphate to be the primary cause of paralysis, various organophosphorus esters including aryl, alkyl, and fluorophosphates have been shown to induce similar effects (reviewed by O'Brien, 1960;Baron, 1962;Heath, 1961;Davies, 1963). The study of the distribution of central and peripheral nervous system lesions, originally described for tri-o-cresyl phosphate by Barnes & Denz (1953), has been extended by other workers to include fluorophosphates (Lancaster, 1960) and a metabolite of tri-o-cresyl phosphate (Baron & Casida, 1962).Tributyl phosphorotrithiolate (DEF) and tributyl phosphorotrithioite (Merphos; Folex) were initially shown by Casida Baron, Eto & Engle (1963) to induce clinical signs of ataxia in hens following a series of intraperitoneal injections. As these two organophosphorus compounds were the first alkyl esters shown to induce signs of delayed neurological ataxia in hens, it was desirable to investigate these effects further.…”

mentioning

confidence: 99%

“…Tributyl phosphorotrithiolate (DEF) and tributyl phosphorotrithioite (Merphos; Folex) were initially shown by Casida Baron, Eto & Engle (1963) to induce clinical signs of ataxia in hens following a series of intraperitoneal injections. As these two organophosphorus compounds were the first alkyl esters shown to induce signs of delayed neurological ataxia in hens, it was desirable to investigate these effects further.…”

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confidence: 99%

Neurological Disruption Produced in Hens by Two Organophosphate Esters

Baron

Johnson

1964

British Journal of Pharmacology and Chemotherapy

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A histological and enzymatic examination was made of the neurological disruption produced in hens by two organophosphate esters. Intraperitoneal administration of DEF (tributyl phosphorotrithiolate) and Merphos (tributyl phosphorotrithioite) produced central and perpheral nervous system lesions accompanied by clinical signs of ataxia similar to those seen following administration of tri-o-cresyl phosphate. Histological examination (utilizing the Marchi stain) showed the occurence of spinal cord disruption before the onset of clinical ataxia. Oral administration of DEF and Merphos did not induce signs of peripheral weakness. However, severe lesions in the spinal cord and sciatic nerve were prominent. A discussion of the occurrence of central and peripheral nerve disruption either in the presence or absence of clinical ataxia is presented. Enzymatic examination of the effect of DEF on spinal cord and brain esterases at various intervals following administration showed a pattern of esterase inhibition similar to that found after tri-o-cresyl phosphate, dyflos and other organophosphates. Some prolonged inhibition is believed due to the extent of initial involvement rather than to selective prolonged inhibition.The delayed neurological effects of certain organophosphorus esters have recently been the subject of extensive study. These neurologically-active compounds have been reported to disrupt myelin (demyelination) of the central and peripheral nervous system in several vertebrate species, including man. From the initial reports on adulterated alcoholic beverages showing tri-o-cresyl phosphate to be the primary cause of paralysis, various organophosphorus esters including aryl, alkyl, and fluorophosphates have been shown to induce similar effects (reviewed by O'Brien, 1960;Baron, 1962;Heath, 1961;Davies, 1963). The study of the distribution of central and peripheral nervous system lesions, originally described for tri-o-cresyl phosphate by Barnes & Denz (1953), has been extended by other workers to include fluorophosphates (Lancaster, 1960) and a metabolite of tri-o-cresyl phosphate (Baron & Casida, 1962).Tributyl phosphorotrithiolate (DEF) and tributyl phosphorotrithioite (Merphos; Folex) were initially shown by Casida Baron, Eto & Engle (1963) to induce clinical signs of ataxia in hens following a series of intraperitoneal injections. As these two organophosphorus compounds were the first alkyl esters shown to induce signs of delayed neurological ataxia in hens, it was desirable to investigate these effects further.

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Potentiation and neurotoxicity induced by certain organophosphates

Cited by 107 publications

References 11 publications

SELECTIVE INHIBITION OF THERMOGENESIS BY TRIBUTYL S,S,S,‐PHOSPHOROTRITHIOATE (DEF)

SELECTIVE INHIBITION OF THERMOGENESIS BY TRIBUTYL S,S,S,‐PHOSPHOROTRITHIOATE (DEF)

Evidence that mouse brain neuropathy target esterase is a lysophospholipase

Neurological Disruption Produced in Hens by Two Organophosphate Esters

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