| First Author | Hoffler U | Year | 2003 |
| Journal | J Pharmacol Exp Ther | Volume | 305 |
| Issue | 2 | Pages | 557-64 |
| PubMed ID | 12704224 | Mgi Jnum | J:124524 |
| Mgi Id | MGI:3721824 | Doi | 10.1124/jpet.102.049072 |
| Citation | Hoffler U, et al. (2003) Cytochrome P450 2E1 (CYP2E1) is the principal enzyme responsible for urethane metabolism: comparative studies using CYP2E1-null and wild-type mice. J Pharmacol Exp Ther 305(2):557-64 |
| abstractText | Urethane ([carbonyl-(14)C]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-(14)C]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. CO(2) was confirmed as the main metabolite of urethane. Significant inhibition of urethane metabolism to CO(2) occurred in CYP2E1-null versus wild-type mice. Pharmacokinetic modeling of (14)CO(2) exhalation data revealed that CYP2E1 is responsible for approximately 96% of urethane metabolism to CO(2) 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 CO(2) in both genotypes. In conclusion, this work demonstrated that CYP2E1, not esterase, is the principal enzyme responsible for urethane metabolism. |
