Cytochrome P450 2E1 (CYP2E1) is the principal enzyme responsible for urethane metabolism: comparative studies using CYP2E1-null and wild-type mice.
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.
Hoffler
Undi
U
Department of Pharmacology, Meharry Medical College, Nashville, Tennessee, USA.
El-Masri
Hisham A
HA
Ghanayem
Burhan I
BI
D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010261:Paraoxon / Q000378:metabolism; D014018:Tissue Distribution; D014230:Triazoles / Q000378:metabolism; D014520:Urethane / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine
D014230:Triazoles; D002245:Carbon Dioxide; C033020:1-aminobenzotriazole; D014520:Urethane; D019392:Cytochrome P-450 CYP2E1; D010261:Paraoxon