Organophosphate polyneuropathy and neuropathy target esterase: Studies with methamidophos and its resolved optical isomers |
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Authors: | M Lotti A Moretto M Bertolazzi M Peraica F Fioroni |
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Institution: | (1) Università degli Studi di Padova, Istituto di Medicina del Lavoro, via Facciolati 71, I-35127 Padova, Italy, IT |
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Abstract: | Methamidophos (O, S-dimethyl phospho rothioamidate) causes polyneuropathy in man and hens. However, experiments in the hen show that lower doses
of methamidophos either protect from or promote the neuropathy caused by certain organophosphates. The initiation of neuropathy
as well as protection from neuropathy are thought to be related to neuropathy target esterase (NTE), whereas promotion is
likely to be due to interactions with another unknown target. Methamidophos is a racemate and we report studies with its resolved
optical isomers, aimed at elucidating which isomer is responsible for the described effects. The time-course of acetylcholinesterase
(AChE) and NTE activity in nervous tissues of hens after inhibition by single doses of either isomer showed that after D-(+)
methamidophos (25 mg/kg PO) peak inhibition of both enzymes was achieved within 24 h (80–90%). However, after L-(−) methamidophos
(15 mg/kg PO), peak inhibition (80–90%) was obtained within 24 h for AChE, whereas similar NTE inhibition (120 mg/kg PO) was
observed only 4 days after dosing. The minimal neuropathic doses of D-(+) and L-(−) methamidophos were 60 and 120 mg/kg PO,
respectively, and correlated with >80% NTE inhibition in nervous tissues. OPIDP initiation by either isomer was slightly promoted
by phenylmethanesulfonyl fluoride (120 mg/kg SC). D-(+) Methamidophos (25 mg/kg PO) partially protected from dibutyl dichlorovinylphosphate
(DBDCVP) neuropathy (up to 0.8 mg/kg SC). This effect correlated with about 70% NTE inhibition. L-(−) Methamidophos (15 or
60 mg/kg PO) did not protect from DBDCVP neuropathy (0.2–0.8 mg/kg SC). D-(+) and L-(−) methamidophos (25 mg/kg PO) promoted
DBDCVP neuropathy (0.4 mg/kg SC), and D-(+) methamidophos (24 mg/kg PO) also promoted DFP neuropathy (0.3 mg/kg SC). These
effects were unrelated to the degree of NTE inhibition they caused: about 70% by D-(+) methamidophos and extrapolated to about
10–15% by L-(−) methamidophos. We conclude that when racemic methamidophos is given to hens, initiation and protection from
OPIDP is due to the interaction of D-(+) methamidophos with NTE. Promotion of OPIDP is due to both isomers as the result of
their interaction with unknown site(s). It is possible that the neuropathy due to racemic methamidophos or isomers is a self
promoted neuropathy because the promoting doses of both isomers are much lower than the neuropathic ones, and because the
neuropathy they initiate is only slightly promoted by phenylmethanesulfonyl fluoride.
Received: 5 July 1994/Accepted: 17 October 1994 |
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Keywords: | Organophosphates Methamidophos Isomers NTE Polyneuropathy Protection Promotion |
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