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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES080055-04
Application #
6432414
Study Section
(LPC)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2000
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Ghanayem, Burhan I; Nyska, Abraham; Haseman, Joseph K et al. (2002) Acrylonitrile is a multisite carcinogen in male and female B6C3F1 mice. Toxicol Sci 68:59-68
Wang, Hongbing; Chanas, Brian; Ghanayem, Burhan I (2002) Cytochrome P450 2E1 (CYP2E1) is essential for acrylonitrile metabolism to cyanide: comparative studies using CYP2E1-null and wild-type mice. Drug Metab Dispos 30:911-7
Ghanayem, B I; Long, P H; Ward, S M et al. (2001) Hemolytic anemia, thrombosis, and infarction in male and female F344 rats following gavage exposure to 2-butoxyethanol. Exp Toxicol Pathol 53:97-105
Ghanayem, B I; Ward, S M; Chanas, B et al. (2000) Comparison of the acute hematotoxicity of 2-butoxyethanol in male and female F344 rats. Hum Exp Toxicol 19:185-92
Long, P H; Maronpot, R R; Ghanayem, B I et al. (2000) Dental pulp infarction in female rats following inhalation exposure to 2-butoxyethanol. Toxicol Pathol 28:246-52
Ghanayem, B I; Wang, H; Sumner, S (2000) Using cytochrome P-450 gene knock-out mice to study chemical metabolism, toxicity, and carcinogenicity. Toxicol Pathol 28:839-50
Ghanayem, B I; Sanders, J M; Chanas, B et al. (1999) Role of cytochrome P-450 2E1 in methacrylonitrile metabolism and disposition. J Pharmacol Exp Ther 289:1054-9
Sumner, S C; Fennell, T R; Moore, T A et al. (1999) Role of cytochrome P450 2E1 in the metabolism of acrylamide and acrylonitrile in mice. Chem Res Toxicol 12:1110-6
Nyska, A; Maronpot, R R; Long, P H et al. (1999) Disseminated thrombosis and bone infarction in female rats following inhalation exposure to 2-butoxyethanol. Toxicol Pathol 27:287-94
Nyska, A; Maronpot, R R; Ghanayem, B I (1999) Ocular thrombosis and retinal degeneration induced in female F344 rats by 2-butoxyethanol. Hum Exp Toxicol 18:577-82