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Research ArticleArticle

PULMONARY BIOACTIVATION OF TRICHLOROETHYLENE TO CHLORAL HYDRATE: RELATIVE CONTRIBUTIONS OF CYP2E1, CYP2F, AND CYP2B1

Poh-Gek Forkert, R. Michael Baldwin, Brandie Millen, Lawrence H. Lash, David A. Putt, Michael A. Shultz and Kathy S. Collins
Drug Metabolism and Disposition October 2005, 33 (10) 1429-1437; DOI: https://doi.org/10.1124/dmd.105.005074
Poh-Gek Forkert
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R. Michael Baldwin
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Brandie Millen
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Lawrence H. Lash
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David A. Putt
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Michael A. Shultz
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Kathy S. Collins
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Abstract

Pulmonary cytotoxicity induced by trichloroethylene (TCE) is associated with cytochrome P450-dependent bioactivation to reactive metabolites. In this investigation, studies were undertaken to test the hypothesis that TCE metabolism to chloral hydrate (CH) is mediated by cytochrome P450 enzymes, including CYP2E1, CYP2F, and CYP2B1. Recombinant rat CYP2E1 catalyzed TCE metabolism to CH with greater affinity than did the recombinant P450 enzymes, rat CYP2F4, mouse CYP2F2, rat CYP2B1, and human CYP2E1. The catalytic efficiencies of recombinant rat CYP2E1 (Vmax/Km = 0.79) for generating CH was greater than those of recombinant CYP2F4 (Vmax/Km = 0.27), recombinant mouse CYP2F2 (Vmax/Km = 0.11), recombinant rat CYP2B1 (Vmax/Km = 0.07), or recombinant human CYP2E1 (Vmax/Km = 0.02). Decreases in lung microsomal immunoreactive CYP2E1, CYP2F2, and CYP2B1 were manifested at varying time points after TCE treatment. The loss of immunoreactive CYP2F2 occurred before the loss of immunoreactive CYP2E1 and CYP2B1. These protein decreases coincided with marked reduction of lung microsomal p-nitrophenol hydroxylation and pentoxyresorufin O-dealkylation. Rates of CH formation in the microsomal incubations were time-dependent and were incremental from 5 to 45 min. The production of CH was also determined in human lung microsomal incubations. The rates were low and were detected in only three of eight subjects. These results showed that, although CYP2E1, CYP2F, and CYP2B1 are all capable of generating CH, TCE metabolism is mediated with greater affinity by recombinant rat CYP2E1 than by recombinant CYP2F, CYP2B1, or human CYP2E1. Moreover, the rates of CH production were substantially higher in murine than in human lung.

Footnotes

  • This study was supported by Assistance Agreement Grant GR828097-01-0 from the U. S. Environmental Protection Agency. The development of the CYP2F1 antibody was supported by Grant HL13645 from the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH). The expression of CYP2F4 and CYP2F2 was performed with support from the National Institute of Environmental Health Sciences, NIH Grant ES 08408. The views expressed in this paper are those of the authors and do not necessarily reflect the views or policies of the U. S. Environmental Protection Agency.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.005074.

  • ABBREVIATIONS: TCE, trichloroethylene; CH, chloral hydrate; DCA, dichloroacetic acid; PNP, p-nitrophenol; rCYP2E1, recombinant CYP2E1; rCYP2F4, recombinant CYP2F4; rCYP2B1, recombinant CYP2B1; TCA, trichloroacetic acid; TCOH, trichloroethanol; HPLC, high-performance liquid chromatography.

    • Received April 10, 2005.
    • Accepted June 24, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (10)
Drug Metabolism and Disposition
Vol. 33, Issue 10
1 Oct 2005
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Research ArticleArticle

PULMONARY BIOACTIVATION OF TRICHLOROETHYLENE TO CHLORAL HYDRATE: RELATIVE CONTRIBUTIONS OF CYP2E1, CYP2F, AND CYP2B1

Poh-Gek Forkert, R. Michael Baldwin, Brandie Millen, Lawrence H. Lash, David A. Putt, Michael A. Shultz and Kathy S. Collins
Drug Metabolism and Disposition October 1, 2005, 33 (10) 1429-1437; DOI: https://doi.org/10.1124/dmd.105.005074

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Research ArticleArticle

PULMONARY BIOACTIVATION OF TRICHLOROETHYLENE TO CHLORAL HYDRATE: RELATIVE CONTRIBUTIONS OF CYP2E1, CYP2F, AND CYP2B1

Poh-Gek Forkert, R. Michael Baldwin, Brandie Millen, Lawrence H. Lash, David A. Putt, Michael A. Shultz and Kathy S. Collins
Drug Metabolism and Disposition October 1, 2005, 33 (10) 1429-1437; DOI: https://doi.org/10.1124/dmd.105.005074
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