US EPA

724936 

Journal Article 

Role Of Cytochrome P450 2E1 (CYP2E1) In Trichloroethylene (TCE) Metabolism And Disposition: Comparative Studies Using CYP2E1-/- And Wild-Type Mice 

Kim, D; Ghanayem, BI 

2005 

1 

Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929 

TOX/5000862 

84 

1-S 

148 

English 

TCE is a known rodent carcinogen and was classified as probable human carcinogen. Metabolism of TCE occurs via glutathione conjugation and CYPs-dependent oxidation. While a number of CYPs were implicated, CYP2E1 is considered the primary high affinity enzyme responsible for TCE metabolism. The objective of this work is to assess the role of CYP2E1 in the metabolism and disposition of TCE using CYP2E1-null (KO) vs. wild type (WT) mice. Mice were administered 1, 2- 14C-TCE by gavage at 1000 mg/kg and placed in glass metabolism cages that allowed for the collection of expired air, urine, and feces. At 24 after dosing, animals were euthanized and blood and tissues were collected and frozen for analysis. Exhalation of TCE derived 14CO2 accounted for 17-18% of dose, and was not significantly different in KO Vs. WT mice. Elimination of TCE-derived organic volatiles in the expired air accounted for 23 and 49% of the administered dose in WT and KO mice, respectively. In contrast, excretion of TCE-derived radioactivity in the urine was approximately 17 and 40% of the administered dose in KO and WT mice, respectively. Pretreatment of mice with 1-aminobenzotriazole (ABT), a universal CYPs inhibitor, prior to TCE administration significantly inhibited 14CO2 exhalation to 2-3%of the administered dose, and increased the exhalation of TCE-derived organic volatiles to 70-77% of the dose in mice of both genotypes. Preliminary analysis suggested that parent TCE is the primary constituent of the expired organic volatiles in ABT pretreated mice. Urinary excretion in ABT-pretreated mice was significantly decreased in KO and WT mice and accounted for approximately 4 and 12% of the dose, respectively. In conclusion, these data suggest that while CYP2E1 plays an important role in TCE metabolism and disposition, other CYPs play an important role as well. Additional studies are in progress to compare the identity of TCE metabolites in the urine and expired air of KO and WT mice in order to quantify the contribution of various CYPs to TCE metabolism 

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