EFFECT OF METHIMAZOLE, AN FMO SUBSTRATE AND COMPETITIVE INHIBITOR, ONTHE NEUROTOXICITY OF 3,3'-IMINODIPROPIONITRILE IN MALE-RATS

This study was designed to examine the role of flavin-containing monoo xygenase (FMO) on the auditory and vestibular neurotoxicity of 3,3'-im inodipropionitrile (IDPN) using the FMO substrate and competitive inhi bitor methimazole (MMI), Specifically, the purpose was to block the FM O-mediated conversion of IDPN to the putative neurotoxic metabolite N- hydroxy 3,3'-iminodipropionitrile (HOIDPN). In three separate experime nts, 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 th e 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 contra st, MMI failed to block, and instead increased, the neurotoxicity asso ciated 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. (C) 1997 Society of Toxic ology.