Received for publication April 14, 2006.
Revised September 5, 2006.
Accepted for publication September 6, 2006.

Comparative metabolism and disposition of trichloroethylene in CYP2E1-/- and Wild-Type Mice

Abstract

Trichloroethylene (TCE)¹ is an important environmental contaminant, a well-established rodent carcinogen, and a "probable human carcinogen." Metabolism of TCE occurs primarily via cytochromes P450 (CYPs)-dependent oxidation. In vitro studies suggested that CYP2E1 is the principal high affinity enzyme responsible for TCE metabolism. The objective of the present work is to more directly assess the role of CYP2E1 in the metabolism and disposition of 1,2-¹⁴C-TCE administered at 250 or 1000 mg/kg (gavage) using Cyp2e1-/- (KO) vs. wild-type (WT) mice. After dosing, animals were individually placed in glass metabolism cages that allowed the collection of expired air, urine, and feces. Exhalation of TCE-derived ¹⁴CO₂ increased in a dose-dependent manner in mice of both genotypes and was significantly higher in WT vs. KO mice. A significantly greater % of the dose was exhaled in KO vs. WT mice as organic volatiles (mainly as TCE). Urinary excretion was the major route of TCE metabolism in WT mice and the % of dose eliminated in urine was significantly higher at the 250 vs. 1000 mg/kg dose. Further, urinary excretion and CO₂ exhalation significantly decreased in KO vs. WT mice. Pretreatment with 1-aminobenzotriazole clearly inhibited TCE metabolism as evident from increased exhalation of parent TCE, and decreased urinary excretion and CO₂ exhalation in mice of both genotypes. In conclusion, these data showed that while CYP2E1 plays an important role in TCE metabolism and disposition, other CYPs also play a significant role and may explain earlier results that showed TCE causes lung damage in KO and WT mice.

Key words: bioactivation, carcinogen metabolism, CYP2E, cytochrome P450 catalyzed oxidations, environmental toxicology, HPLC