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Research ArticleArticle

Species- and Sex-Related Differences in Metabolism of Trichloroethylene To Yield Chloral and Trichloroethanol in Mouse, Rat, and Human Liver Microsomes

Adnan A. Elfarra, Renee J. Krause, Allen R. Last, Lawrence H. Lash and Jean C. Parker
Drug Metabolism and Disposition August 1998, 26 (8) 779-785;
Adnan A. Elfarra
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Renee J. Krause
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Allen R. Last
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Lawrence H. Lash
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Jean C. Parker
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Abstract

Trichloroethylene (TRI) has been shown to cause a variety of tumors, particularly in mouse liver and lung and rat kidney. However, a clear association between exposure to TRI and cancer development in humans has not been established. Because TRI metabolism by cytochrome P450s has been implicated in the mechanisms of TRI-induced carcinogenicity in mice, the purpose of the present study was to characterize the kinetics of TRI oxidation in male and female mouse, rat, and human liver microsomes to possibly allow for a better assessment of human risk. Methods were developed to detect and quantitate chloral, trichloroethanol, trichloroacetic acid, dichloroacetic acid, chloroacetic acid, glyoxylic acid, and oxalic acid, known TRI metabolites in rodents or humans. However, only chloral and its further metabolite, trichloroethanol, were consistently detected in the various liver microsomes in the presence of NADPH. Chloral was the major metabolite detected, and its levels were species- and sex-dependent; the amounts of trichloroethanol detected were also species- and sex-dependent but never exceeded 15% of total metabolites. Double-reciprocal plots of metabolite formation with male and female rat and human liver microsomes indicated biphasic kinetics, but this trend was not observed with microsomes from male or female mouse liver. The Vmax data are consistent, with male and female mice being more susceptible to TRI-induced liver carcinogenicity than male rats. However, theVmax/Kmratios in male and female rat liver microsomes, in comparison with the male mouse liver microsomes, did not correlate with tumor incidences in these tissues. Furthermore, as only two out of six human liver samples examined exhibitedVmax/Kmratios similar or higher than the ratio obtained with male mouse liver, humans may vary in their toxic response after TRI exposure.

Footnotes

  • Send reprint requests to: Dr. Adnan A. Elfarra, Department of Comparative Biosciences, University of Wisconsin School of Veterinary Medicine, 2015 Linden Drive West, Madison, WI 53706.

  • This study was supported by cooperative agreements with the U.S. Environmental Protection Agency (CR-822240 and CR-824183). The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency.

  • Abbreviations used are::
    TRI
    trichloroethylene
    TCE
    trichloroethanol
    CAA
    chloroacetic acid
    DCA
    dichloroacetic acid
    TCA
    trichloroacetic acid
    GLY
    glyoxylic acid
    OXA
    oxalic acid
    GC
    gas chromatography.
    • Received January 30, 1998.
    • Accepted April 29, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 8
1 Aug 1998
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Research ArticleArticle

Species- and Sex-Related Differences in Metabolism of Trichloroethylene To Yield Chloral and Trichloroethanol in Mouse, Rat, and Human Liver Microsomes

Adnan A. Elfarra, Renee J. Krause, Allen R. Last, Lawrence H. Lash and Jean C. Parker
Drug Metabolism and Disposition August 1, 1998, 26 (8) 779-785;

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Research ArticleArticle

Species- and Sex-Related Differences in Metabolism of Trichloroethylene To Yield Chloral and Trichloroethanol in Mouse, Rat, and Human Liver Microsomes

Adnan A. Elfarra, Renee J. Krause, Allen R. Last, Lawrence H. Lash and Jean C. Parker
Drug Metabolism and Disposition August 1, 1998, 26 (8) 779-785;
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