El lugar y molécula diana de la polineuropatia retardada inducida por organofosforados (OPIDN)

Abstract

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 termináis. 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 "¡n vitro" by a series of chiral phosphoramidates (O-alkyl, 0-2,5,diclofophenyl phosphoramidates; alkyl-DCP) dit not age after 19h. However 19h after appropríate 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" ¡nteracts 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