Mechanism of neurotoxic action of beta,beta'-iminodipropionitrile (IDPN): N-hydroxylation enhances neurotoxic potency.
The molecular mechanism(s) whereby beta, beta'-iminodipropionitrile (IDPN) induces an excitatory behavioral syndrome and a distinct alteration of the axonal cytoskeleton in experimental animals is not known. We demonstrate here that upon intraperitoneal administration to rats, the N-hydroxy analog of IDPN (HOIDPN) induces a parallel spectrum of both neurotoxic effects of IDPN and is approximately 8 times more potent than IDPN in this regard. This is consistent with the involvement of a flavin monooxygenase-mediated N-oxygenation pathway in the toxic activation of IDPN.
Morandi
A
A
Division of Neuropathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106.
Gambetti
P
P
Arora
P K
PK
Sayre
L M
LM
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000648:ultrastructure; D001522:Behavior, Animal / Q000187:drug effects; D001696:Biomechanical Phenomena; D006900:Hydroxylation; D008297:Male; D009498:Neurotoxins / Q000494:pharmacology*; D009570:Nitriles / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012584:Sciatic Nerve / Q000187:drug effects / Q000648:ultrastructure; D013116:Spinal Cord / Q000187:drug effects / Q000648:ultrastructure; D013979:Tibial Nerve / Q000187:drug effects / Q000648:ultrastructure
D009498:Neurotoxins; D009570:Nitriles; C008110:3,3'-iminodipropionitrile