Biological Activity of a Tri-o-Cresyl Phosphate Metabolite

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

doi:10.1038/1911396a0

Cited by 153 publications

(66 citation statements)

References 11 publications

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“…Since TOCP is thought to be metabolised into active (in terms of ability to induce OPIDN) congeners such as saligenin cyclic-O-tolyl phosphate (SCOTP) [24][25][26][27] …”

Section: Introductionmentioning

confidence: 99%

Inhibition of neurite outgrowth in differentiating mouse N2a neuroblastoma cells by phenyl saligenin phosphate: Effects on MAP kinase (ERK 1/2) activation, neurofilament heavy chain phosphorylation and neuropathy target esterase activity

Hargreaves

Fowler

Sachana

et al. 2006

Biochemical Pharmacology

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“…Since TOCP is thought to be metabolised into active (in terms of ability to induce OPIDN) congeners such as saligenin cyclic-O-tolyl phosphate (SCOTP) [24][25][26][27] …”

Section: Introductionmentioning

confidence: 99%

Inhibition of neurite outgrowth in differentiating mouse N2a neuroblastoma cells by phenyl saligenin phosphate: Effects on MAP kinase (ERK 1/2) activation, neurofilament heavy chain phosphorylation and neuropathy target esterase activity

Hargreaves

Fowler

Sachana

et al. 2006

Biochemical Pharmacology

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“…The delayed neurotoxicity of this triaryl phosphate involves bioactivation to the o-tolyloxy derivative of benzodioxaphosphorin oxide (BDPO; ref. 9). Other OP delayed neurotoxicants are the insecticide mipafox, which is no longer used (4,5), and the cotton defoliant tribufos (10).…”

mentioning

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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“…The big difference between J PHa and J pHb (~J=12~14Hz) in the saligenin cyclic phosphoramidates (6~9) suggests that they exist mainly in one conformation in CDCI 3 The sum of coupling constants of phosphorus with two methylene protons is nearly constant: 28.7 (a= 1.30) and 28.1 (a=0.59) Hz on average for the phosphonates and phosphoramidates, respectively.…”

Section: C2mentioning

confidence: 80%

“…3 (8) 349 (22) 36 (6) 10 (5) 338 (17) 6 (4) 13 (5) 344 (18) 8 (4) -I (6) 278 (19) -8 (5) 37 (10) 408 (24) 47 (7) s C8 a reference. Three-dimensional intensity data of X -ray diffraction were collected on a Hilger and Watts automatic four-circle Y290 diffractometer controlled by a PDP8 fractional atomic coordinates and thermal parameters are listed in Table I.…”

Section: C2mentioning

confidence: 99%