Gavage administration of MAN to rats causes olfactory epithelial metaplasia and necrosis. In rats, MAN is metabolized to acetone which is eliminated along with parent MAN in breath. Since acetone is a known inducer of CYP2E1, we hypothesized that acetone exhalation may result in increased expression of CYP2E1 in the olfactory tissue leading to increased in situ formation of cytotoxic MAN metabolites. To address this hypothesis, male F344 rats received 60 mg MAN /kg and were sacrificed 6, 12, or 24 hr after a single dose, or 24 hr after 7 consecutive daily doses. RT-PCR, Western blotting, and immunohistochemical staining were used to determine CYP2E1 expression, and chlorzoxazone hydroxylation was used to assess CYP2E1 catalytic activity. Present results showed that CYP2E1 mRNA was increased in lung and olfactory tissues with minimal effect in the liver. Further, CYP2E1 protein expression increased in lung, olfactory, and liver tissues. These data showed that administration of MAN to rats causes increased expression of CYP2E1 in lung and olfactory. These results also showed that acetone, similar to MAN, induces the expression of CYP2E1 at both the transcriptional and post-transcriptional levels in rat nasal and lung tissues. Further, under the conditions used in this work, increased expression of CYP2E1 in the liver of MAN-treated rats is apparently limited to post-transcriptional mechanisms.
