Document Detail


Pharmacokinetic analysis of trichloroethylene metabolism in male B6C3F1 mice: Formation and disposition of trichloroacetic acid, dichloroacetic acid, S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-L-cysteine.
MedLine Citation:
PMID:  19409406     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Trichloroethylene (TCE) is a well-known carcinogen in rodents and concerns exist regarding its potential carcinogenicity in humans. Oxidative metabolites of TCE, such as dichloroacetic acid (DCA) and trichloroacetic acid (TCA), are thought to be hepatotoxic and carcinogenic in mice. The reactive products of glutathione conjugation, such as S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and S-(1,2-dichlorovinyl) glutathione (DCVG), are associated with renal toxicity in rats. Recently, we developed a new analytical method for simultaneous assessment of these TCE metabolites in small-volume biological samples. Since important gaps remain in our understanding of the pharmacokinetics of TCE and its metabolites, we studied a time-course of DCA, TCA, DCVG and DCVG formation and elimination after a single oral dose of 2100 mg/kg TCE in male B6C3F1 mice. Based on systemic concentration-time data, we constructed multi-compartment models to explore the kinetic properties of the formation and disposition of TCE metabolites, as well as the source of DCA formation. We conclude that TCE-oxide is the most likely source of DCA. According to the best-fit model, bioavailability of oral TCE was approximately 74%, and the half-life and clearance of each metabolite in the mouse were as follows: DCA: 0.6 h, 0.081 ml/h; TCA: 12 h, 3.80 ml/h; DCVG: 1.4 h, 16.8 ml/h; DCVC: 1.2 h, 176 ml/h. In B6C3F1 mice, oxidative metabolites are formed in much greater quantities (approximately 3600 fold difference) than glutathione-conjugative metabolites. In addition, DCA is produced to a very limited extent relative to TCA, while most of DCVG is converted into DCVC. These pharmacokinetic studies provide insight into the kinetic properties of four key biomarkers of TCE toxicity in the mouse, representing novel information that can be used in risk assessment.
Authors:
Sungkyoon Kim; David Kim; Gary M Pollack; Leonard B Collins; Ivan Rusyn
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-05-03
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  238     ISSN:  1096-0333     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-06-05     Completed Date:  2009-06-22     Revised Date:  2014-09-15    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  90-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Animals
Biological Availability
Carcinogens / pharmacokinetics*
Cysteine / analogs & derivatives,  pharmacokinetics
Dichloroacetic Acid / pharmacokinetics
Glutathione / analogs & derivatives,  metabolism*,  pharmacokinetics
Half-Life
Male
Mice
Models, Biological*
Oxidation-Reduction
Risk Assessment
Time Factors
Trichloroacetic Acid / pharmacokinetics
Trichloroethylene / pharmacokinetics*
Grant Support
ID/Acronym/Agency:
P30 ES010126/ES/NIEHS NIH HHS; P30 ES010126-049007/ES/NIEHS NIH HHS; P42 ES005948/ES/NIEHS NIH HHS; P42 ES005948/ES/NIEHS NIH HHS; P42 ES005948-160010/ES/NIEHS NIH HHS; R01 ES015241/ES/NIEHS NIH HHS; R01 ES015241-02/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Carcinogens; 290YE8AR51/Trichloroethylene; 5V2JDO056X/Trichloroacetic Acid; 627-72-5/S-(1,2-dichlorovinyl)cysteine; 96614-59-4/S-(1,2-dichlorovinyl)glutathione; 9LSH52S3LQ/Dichloroacetic Acid; GAN16C9B8O/Glutathione; K848JZ4886/Cysteine
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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