El lugar y molécula diana de la polineuropatia retardada inducida por organofosforados (OPIDN)
1989
Some organophosphorus compounds (OPs), after a single dose, can
induce an effect non related with cholinesterase inhibition and called OP
Induced Delayed Polyneuropathy (OPIDP). We have developed an experimen
tal model of "in situ" local dosing on a 1.5 cm length segment of hen sciatic
nerve, with the purpose of getting answer to the question: what is the cellular
target site for the mecanism of initiation of the OPIDP?. The local dosing of
25-100 micrograms (150-600 nmols) of di-iso-propyl phosphoro fluoridate (DFP)
caused the loss of the leg retraction reflex, a characteristic peripheral effect. It
is suggested that the OPIDP can be initiate by a Irreversible biochemical insult
on a segment of the axonal fiber, without initial involvement of perikaryon or
terminais. The organophosphorylation and the further specific modification of
the so-called "aging" process (dealkylation of the group P-O-R) of a protein
named NTE, is considered the molecular event that initiates OPIDP. This aging
process can be detected operationally by the loss of the ability of being
reactivated by KF. NTE organophosphorylated "in vitro" by a series of chiral
phosphoramidates (O-alkyl, 0-2,5,diclofophenyl phosphoramidates; alkyl-DCP)
dit not age after 19h. However 19h after appropriate p.o. dose, the "in vivo"
phosphorylated NTE could not be reactivated by KF, proving that the aging
process have occurred. The differences showed that the molecular species that
works "in vitro" and "in vivo" are different, and that the compound which remains
"in vivo" interacts with NTE with the stereospecificity needed to modify NTE in
the appropriate manner to induce neuropathy. This have been confirmed by
toxicological tests. The role of the stereospecificity of the biotransformation on
OPs toxicity are discussed, and data are showed proving the difference between
rat and hen in the biotransformationof paraoxon and hexyl-DCP
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