Effect of methimazole, an FMO substrate and competitive inhibitor, on the neurotoxicity of 3,3'-iminodipropionitrile in male rats.
This study was designed to examine the role of flavin-containing monooxygenase (FMO) on the auditory and vestibular neurotoxicity of 3,3'-iminodipropionitrile (IDPN) using the FMO substrate and competitive inhibitor methimazole (MMI). Specifically, the purpose was to block the FMO-mediated conversion of IDPN to the putative neurotoxic metabolite N-hydroxy3,3'-iminodipropionitrile (HOIDPN). In three separate experiments, adult male Long-Evans hooded rats were administered (ip) saline (vehicle), MMI, IDPN, or HOIDPN individually, or a combination of IDPN and MMI or HOIDPN and MMI. Animals were observed daily for signs of the ECC syndrome (excitation with choreiform and circling movements) for 10 days. One to 2 weeks after exposure, a battery of behavioral tests was used to examine vestibular and auditory function. MMI completely blocked the neurotoxicity associated with a 600 mg/kg dose of IDPN and partially blocked the effects of a 1000 mg/kg dose of IDPN. In contrast, MMI failed to block, and instead increased, the neurotoxicity associated with HOIDPN. These data suggest that FMO-mediated metabolism of IDPN is necessary for the generation of a metabolite responsible for the vestibular and auditory neurotoxicities.
Nace
C G
CG
Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, US EPA, Research Triangle Park, NC 27711, USA.
Genter
M B
MB
Sayre
L M
LM
Crofton
K M
KM
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006309:Hearing / Q000187:drug effects; D008297:Male; D008713:Methimazole / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009570:Nitriles / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010105:Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D014724:Vestibular Function Tests; D014725:Vestibular Nerve / Q000187:drug effects* / Q000201:enzymology; D014722:Vestibule, Labyrinth / Q000502:physiology; D000159:Vestibulocochlear Nerve / Q000187:drug effects* / Q000201:enzymology
D004791:Enzyme Inhibitors; D009498:Neurotoxins; D009570:Nitriles; C101867:N-hydroxy-3,3'-iminodipropionitrile; C008110:3,3'-iminodipropionitrile; D008713:Methimazole; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)