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Drug Metabolism and Disposition Fast Forward
First published on May 6, 2005; DOI: 10.1124/dmd.105.003806

0090-9556/05/3308-1144-1150$20.00
DMD 33:1144-1150, 2005

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INCREASED BIOACCUMULATION OF URETHANE IN CYP2E1-/- VERSUS CYP2E1+/+ MICE

Undi Hoffler, and Burhan I. Ghanayem

Department of Pharmacology, Meharry Medical College, Nashville, Tennessee; and Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina

Urethane is a fermentation by-product and a potent animal carcinogen. Human exposure to urethane occurs through consumption of alcoholic beverages and fermented foods. Recently, CYP2E1 was identified as the primary enzyme responsible for the metabolism of [14C]carbonyl-labeled urethane. Subsequently, attenuation of urethane-induced cell proliferation and genotoxicity in CYP2E1-/- mice was reported. The present work compares the metabolism of single versus multiple exposures of CYP2E1-/- and CYP2E1+/+ mice to 14C-ethyl-labeled urethane. Urethane was administered as a single 10 or 100 mg/kg gavage dose or at 100 mg/kg/day for 5 consecutive days. CYP2E1+/+ mice administered single or multiple doses exhaled 78 to 88% of dose as 14CO2/day. CYP2E1-/- mice eliminated 30 to 38% of a single dose as 14CO2 in 24 h and plateaued after day 3 at {approx}52% of dose/day. The concentrations of urethane-derived radioactivity in plasma and tissues were dose-dependent, increased as a function of the number of doses administered, and were significantly higher in CYP2E1-/- versus CYP2E1+/+ mice. Whereas urethane was the main chemical found in the plasma and tissues of CYP2E1-/- mice, it was not detectable in CYP2E1+/+ mice. In conclusion, multiple dosing led to considerable bioaccumulation of urethane in mice of both genotypes; however, greater retention occurred in CYP2E1-/- versus CYP2E1+/+ mice. Furthermore, greater bioaccumulation of 14C-ethyl-labeled than [14C]carbonyl-labeled urethane was observed in mice. Comparison of the metabolism of ethyl-versus carbonyl-labeled urethane was necessary for tracing the source of CO2 and led us to propose for the first time that C-hydroxylation is a likely pathway of urethane metabolism.

Address correspondence to: Dr. Burhan I. Ghanayem, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709. E-mail: ghanayem{at}niehs.nih.gov




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 Toxicol SciHome page
B. I. Ghanayem
Inhibition of Urethane-Induced Carcinogenicity in Cyp2e1-/- in Comparison to Cyp2e1+/+ Mice
Toxicol. Sci., February 1, 2007; 95(2): 331 - 339.
[Abstract] [Full Text] [PDF]


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