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Research ArticleArticle

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

Undi Hoffler and Burhan I. Ghanayem
Drug Metabolism and Disposition August 2005, 33 (8) 1144-1150; DOI: https://doi.org/10.1124/dmd.105.003806
Undi Hoffler
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Burhan I. Ghanayem
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Abstract

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 ≈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.

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  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.003806.

  • ABBREVIATIONS: P450, cytochrome P450; HPLC, high performance liquid chromatography; VC, vinyl carbamate; VCE, vinyl carbamate epoxide.

    • Received January 24, 2005.
    • Accepted May 3, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (8)
Drug Metabolism and Disposition
Vol. 33, Issue 8
1 Aug 2005
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Research ArticleArticle

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

Undi Hoffler and Burhan I. Ghanayem
Drug Metabolism and Disposition August 1, 2005, 33 (8) 1144-1150; DOI: https://doi.org/10.1124/dmd.105.003806

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Research ArticleArticle

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

Undi Hoffler and Burhan I. Ghanayem
Drug Metabolism and Disposition August 1, 2005, 33 (8) 1144-1150; DOI: https://doi.org/10.1124/dmd.105.003806
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