Metabolites of Trichloroethylene
Abstract
Trichloroacetic acid (TCA) is a metabolite of trichloroethylene (TRI) thought to contribute to its hepatocarcinogenic effects in mice. Recent studies have shown that peak blood concentrations of TCA do not occur until ∼12 hr after an oral dose of TRI; however, blood concentrations of TRI reach a maximum within 1 hr and is nondetectable after 2 hr. The objective of this study was to examine quantitatively enterohepatic recirculation of trichloroethanol (TCEOH) and TCA as a possible mechanism responsible for the delayed production of TCA. Jugular vein, duodenum, and bile duct-cannulated Fischer 344 rats were used, with the collection of blood, bile, urine, and feces samples after intraduodenal and intravenous dosing of animals with TRI, TCEOH, and TCA. Samples were analyzed by GC for TCA, total TCEOH, and free TCEOH. The results show that, after an intravenous dose of TCEOH (100 mg/kg), 36% of the TCEOH in blood is attributable to enterohepatic recirculation. With the same treatment, 76% of the TCA in blood is attributable to enterohepatic recirculation of metabolites. Peak concentrations of total TCEOH in bile, after an intraduodenal dose of TRI, are over 5 times higher than peak concentrations of total TCEOH in systemic blood. Peak concentrations of TCEOH glucuronide in bile are ∼200 times higher than peak concentrations of TCEOH glucuronide in systemic blood.
Footnotes
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Send reprint requests to: R. D. Stenner, Pacific Northwest National Laboratory, P.O. Box 999, MSIN K3-54, Richland, WA 99352.
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This work was supported in part by the U.S. Environmental Protection Agency (CR 819283-02).
- Abbreviations used are::
- TRI
- trichloroethylene
- TCA
- trichloroacetic acid
- DCA
- dichloroacetic acid
- TCEOH
- trichloroethanol
- DCPA
- 2,2-dichloropropionic acid
- F-344
- Fischer 344
- GC
- gas chromatograph
- Kelim
- elimination rate constant
- AUC
- area under the concentration-time curve
- PBPK
- physiologically based pharmacokinetic
- Received April 5, 1996.
- Accepted January 9, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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