Inhibition of chicken brain neurotoxic esterase (NTE) by a series of
O-halogenated-phenyl-
O-alkyl phenylphosphonates was studied
in vitro. The “apparent” activity was found to consist of “true” NTE (sensitive to mipafox) plus a minor mipafox-resistant component. The pI
50 of
O-(2,6-dichlorophenyl)
O-methyl phenylphosphonate for “true” NTE was 6.65, whereas it was about 3 for mipafox-resistant hydrolysis of phenyl valerate. This compound is suitable as an alternative to mipafox in the assay of “true” NTE, whereas the use of leptophos oxon gives a less accurate measure. The ethoxy analogs are about as potent
in vitro as the corresponding methoxy compounds. Leptophosoxon and ethoxyleptophosoxon are more potent
in vitro inhibitors than desbromoleptophosoxon. Within a like group of chlorinated phenylphosphonates, a reasonable correlation between
in vitro neurotoxic esterase inhibition of the oxon and
in vivo delayed neurotoxic potential by the corresponding phosphonothionate exists.
In vivo inhibition of “apparent” NTE from chicken brain, studied 24 hr after an oral dose, is dose dependent for leptophos, ethoxyleptophos, and desbromoleptophos, the latter one being a very potent
in vivo inhibitor. Ethoxyleptophos and leptophos have about equal
in vivo esterase inhibitory properties. For desbromoleptophos and leptophos there is good agreement between the minimum dose causing delayed neurotoxicity and the dose leading to substantial inhibition of “apparent” NTE; ethoxyleptophos, on the other hand, inhibits the esterase at a dose much lower than the one which is neurotoxic. Several possible explanations for this discrepancy are considered.
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