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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Cytochrome P450 2E1 (CYP2E1) Is the Principal Enzyme Responsible for Urethane Metabolism: Comparative Studies Using CYP2E1-Null and Wild-Type Mice

Undi Hoffler, Hisham A. El-Masri and Burhan I. Ghanayem
Journal of Pharmacology and Experimental Therapeutics May 2003, 305 (2) 557-564; DOI: https://doi.org/10.1124/jpet.103.049072
Undi Hoffler
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Hisham A. El-Masri
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Burhan I. Ghanayem
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This article has a correction. Please see:

  • Correction to “Cytochrome P450 2E1 (CYP2E1) Is the Principal Enzyme Responsible for Urethane Metabolism: Comparative Studies Using CYP2E1-Null and Wild-Type Mice” - December 01, 2003

Abstract

Urethane ([carbonyl-14C]ethyl carbamate) is a fermentation by-product in alcoholic beverages and foods and is classified as reasonably anticipated to be a human carcinogen. Early studies indicated that while CYP2E1 is involved, esterases are the primary enzymes responsible for urethane metabolism. Using CYP2E1-null (KO) mice, current studies were undertaken to elucidate CYP2E1's contribution to urethane metabolism. [Carbonyl-14C]urethane was administered by gavage to male CYP2E1-null and wild-type mice at 10 or 100 mg/kg and its metabolism and disposition were investigated. CO2 was confirmed as the main metabolite of urethane. Significant inhibition of urethane metabolism to CO2 occurred in CYP2E1-null versus wild-type mice. Pharmacokinetic modeling of14CO2 exhalation data revealed that CYP2E1 is responsible for approximately 96% of urethane metabolism to CO2 in wild-type mice. The contributions of other enzymes to urethane metabolism merely account for the remaining 4%. The half-life of urethane in wild-type and CYP2E1-null mice was estimated at 0.8 and 22 h, respectively. Additionally, the concentration of urethane-derived radioactivity in blood and tissues was dose-dependent and significantly higher in CYP2E1-null mice. High-performance liquid chromatography analysis showed only urethane in the plasma and liver extracts of CYP2E1-null mice. Because the lack of CYP2E1 did not completely inhibit urethane metabolism, the disposition of 10 mg/kg urethane was compared in mice pretreated with the P450 inhibitor, 1-aminobenzotriazole or the esterase inhibitor, paraoxon. Unlike paraoxon, 1-aminobenzotriazole resulted in significant inhibition of urethane metabolism to CO2 in both genotypes. In conclusion, this work demonstrated that CYP2E1, not esterase, is the principal enzyme responsible for urethane metabolism.

Footnotes

  • Portions of this work were presented at the 41st Annual Society of Toxicology meeting in Nashville, TN, March 2002. The presented work is in partial fulfillment of Undi Hoffler's Ph.D. dissertation research.

  • DOI: 10.1124/jpet.102.049072

  • Abbreviations:
    P450
    cytochrome P450
    CYP2E1-null
    cytochrome P450 2E1-null mice
    urethane
    [carbonyl-14C]ethyl carbamate
    HPLC
    high-performance liquid chromatography
    ABT
    1-aminobenzotriazole
    VC
    vinyl carbamate
    PAX
    paraoxon
    WT
    wild-type
    KO
    CYP2E-null
    • Received January 9, 2003.
    • Accepted January 15, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 2
1 May 2003
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Cytochrome P450 2E1 (CYP2E1) Is the Principal Enzyme Responsible for Urethane Metabolism: Comparative Studies Using CYP2E1-Null and Wild-Type Mice

Undi Hoffler, Hisham A. El-Masri and Burhan I. Ghanayem
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 557-564; DOI: https://doi.org/10.1124/jpet.103.049072

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Cytochrome P450 2E1 (CYP2E1) Is the Principal Enzyme Responsible for Urethane Metabolism: Comparative Studies Using CYP2E1-Null and Wild-Type Mice

Undi Hoffler, Hisham A. El-Masri and Burhan I. Ghanayem
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 557-564; DOI: https://doi.org/10.1124/jpet.103.049072
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