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Research ArticleArticle

Diminished CYP2E1 Expression and Formation of 2-S-Glutathionyl Acetate, a Glutathione Conjugate Derived from 1,1-Dichloroethylene Epoxide, in Murine Lung Tumors

Poh-Gek Forkert, Alvin M. Malkinson, Pamela Rice and Madeleine Moussa
Drug Metabolism and Disposition January 1999, 27 (1) 68-73;
Poh-Gek Forkert
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Alvin M. Malkinson
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Pamela Rice
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Madeleine Moussa
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Abstract

We hypothesized that resistance of lung tumors to the cytotoxic effects of xenobiotics is associated with loss of cytochrome P-450 expression, leading to defective formation of reactive intermediates. To test this hypothesis, we investigated 1,1-dichloroethylene (DCE), a chemical that causes Clara cell damage, in a urethane-induced model of lung tumorigenesis. Lung metabolism of DCE yields 2-S-glutathionyl acetate (conjugate [C]), a glutathione conjugate derived from DCE-epoxide, believed to be the ultimate toxic species. We used immunohistochemistry to investigate CYP2E1 expression in nontumor- and tumor-bearing lung to identify cells capable of generating [C]. CYP2E1 and [C] were colocalized in adjacent tissue sections to determine coincidence between CYP2E1 and [C] in lung cells. CYP2E1 was highly localized to the bronchiolar epithelium of nontumor-bearing lung and in uninvolved tissue of tumor-bearing lung and was concentrated in the Clara cells. In contrast, tumor foci including hyperplasias, adenomas, and carcinomas were deficient in CYP2E1 in both untreated and DCE-treated mice. Immunoreactivity for [C] was also detected in the bronchiolar epithelium in nontumor-bearing lung and uninvolved tissue of tumor-bearing lung of DCE-treated mice and was reduced in hyperplasias, adenomas, or carcinomas. Thus, there was a coincidence between the sites of CYP2E1 expression and [C] formation. Conjugate [C] accumulated only in lung cells in which CYP2E1 was expressed. Histochemical staining for glutathione confirmed its presence in tumor foci. Thus, bioactivation and conjugation of DCE occur in structurally normal tissue from both nontumor- and tumor-bearing lung but was lost in tumor tissue, irrespective of the stage of tumor development.

Footnotes

  • Send reprint requests to: Poh-Gek Forkert, Department of Anatomy and Cell Biology, Queen’s University, Kingston, Ontario, Canada K7L 3N6. e-mail: forkertp{at}post.queensu.ca

  • This research was supported by Grant MT-11706 from the Medical Research Council of Canada (P.G.F.) and Grant RO1 CA73220-01 from the National Cancer Institute, National Institutes of Health (P.G.F.). A preliminary report of this study was presented at the Second International Lung Tumorigenesis Symposium, June 19, 1997, in Columbus, OH.

  • Abbreviations used are::
    BSA
    bovine serum albumin
    DCE
    1,1-dichloroethylene
    GSH
    glutathione
    [C]
    2-S-glutathionyl acetate
    PBS
    phosphate-buffered saline
    • Received May 11, 1998.
    • Accepted July 27, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (1)
Drug Metabolism and Disposition
Vol. 27, Issue 1
1 Jan 1999
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Research ArticleArticle

Diminished CYP2E1 Expression and Formation of 2-S-Glutathionyl Acetate, a Glutathione Conjugate Derived from 1,1-Dichloroethylene Epoxide, in Murine Lung Tumors

Poh-Gek Forkert, Alvin M. Malkinson, Pamela Rice and Madeleine Moussa
Drug Metabolism and Disposition January 1, 1999, 27 (1) 68-73;

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Research ArticleArticle

Diminished CYP2E1 Expression and Formation of 2-S-Glutathionyl Acetate, a Glutathione Conjugate Derived from 1,1-Dichloroethylene Epoxide, in Murine Lung Tumors

Poh-Gek Forkert, Alvin M. Malkinson, Pamela Rice and Madeleine Moussa
Drug Metabolism and Disposition January 1, 1999, 27 (1) 68-73;
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