Increased bioaccumulation of Urethane in CYP2E1-/- vs. CYP2E1+/+ Mice

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 C-carbonyl-labeled urethane. Subsequently, attenuation of urethaneinduced cell proliferation and genotoxicity in CYP2E1-/mice was reported. Present work compares the metabolism of single vs. multiple exposures of CYP2E1-/and CYP2E1+/+ mice to C-ethyl-labeled urethane. Urethane was administered as a single 10 or 100mg/kg gavage dose or at 100mg/kg/day for 5 consecutive days. CYP2E1+/+ mice administered single or multiple doses exhaled 78-88% of dose as CO2/day. CYP2E1-/mice eliminated 30-38% of a single dose as CO2 in 24hr 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-/vs. CYP2E1+/+ mice. While 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-/vs. CYP2E1+/+ mice. Further, greater bioaccumulation of C-ethyl-labeled than C-carbonyl-labeled urethane was observed in mice. Comparison of the metabolism of ethylvs. 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. This article has not been copyedited and formatted. The final version may differ from this version. DMD Fast Forward. Published on May 6, 2005 as DOI: 10.1124/dmd.105.003806 at A PE T Jornals on A ril 2, 2017 dm d.aspurnals.org D ow nladed from