EFFECTS OF P450 INHIBITION AND INDUCTION ON THE OLFACTORY TOXICITY OFBETA,BETA'-IMINODIPROPIONITRILE (IDPN) IN THE RAT

In addition to the neurotoxic effects of beta,beta'-iminodipropionitri le (IDPN) which have been previously reported by other investigators, the olfactory toxicity of this compound has recently been uncovered in this laboratory. Due to the apparently conflicting observations that the IDPN-induced lesion in the olfactory mucosatis very focal in natur e (suggesting site-specific activation) and the observation by other i nvestigators that the behavioral effects of IDPN appear to be due to t he parent compound, we initiated studies into the possible role of the cytochrome P450 enzymes in the olfactory toxicity of IDPN. Immunohist ochemical studies with antibodies raised against several different P45 0 isoforms revealed good correlation between IDPN-induced olfactory mu cosal degeneration and the localization of a protein immunoreacting wi th an antibody to P450 2E1. Enzymatic studies revealed that there is a pproximately five-fold more p-nitrophenol hydroxylation activity in th e olfactory mucosa than in the liver on a per milligram microsomal pro tein basis. Administration of 1% acetone in the drinking water increas ed the levels of olfactory mucosal 2E1, and the increase in enzyme lev els corresponded to increased olfactory toxicity of IDPN; inhibition o f P450 activities with either metyrapone or carbon tetrachloride elimi nated or significantly decreased the olfactory toxicity of IDPN, respe ctively. These studies suggest a role for cytochrome P450, specificall y the 2E1 isoform, in the activation of IDPN within the nasal mucosa.