Abstract

of Work: Methacrylonitrile (MAN) is a widely used aliphatic nitrile which is structurally similar to the known rat carcinogen, and suspected human carcinogen, acrylonitrile (AN). There is evidence that AN and MAN are metabolized via the cytochrome P450 enzymes. We recently identified 2 biliary conjugates originating from the interaction of MAN and its epoxide with glutathione. Mercapturic acids formed via the degradation of the 2 conjugates were also identified in rat and mouse urine. Additionally, a significant portion of MAN was eliminated in the expired air as CO2 (formed via the epoxide pathway) and unchanged MAN. The objective of the present work is to determine if CYP2E1 is involved in MAN metabolism as it was suggested for AN. 2-14C-MAN was administered to CYP2E1 -/- or CYP2E1 +/+ mice by gavage at 12 mg/kg. While CYP2E1- null animals exhaled greater than 30% of the administered dose as unchanged MAN, wild-type animals exhaled 1-3% of the dose as such. Additionally, CYP3E1-null and wild animals exhaled approximately 30 and 10% of the dose as CO2, respectively. Urinary and fecal excretion of MAN-derived metabolites were relatively similar in both CYP2E1-null and wild-type animals; however, preliminary analysis showed significant qualitative differences in the ratio of various metabolites on MAN in the urine.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES080055-01
Application #
6162310
Study Section
Special Emphasis Panel (LPC)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
National Institute of Environmental Health Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

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