QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) An erratum has been published All Versions of this Article: jpet.104.068171v1 jpet.104.068171v2 310/3/855    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Simmonds, A. C. Articles by Forkert, P.-G. Search for Related Content PubMed PubMed Citation Articles by Simmonds, A. C. Articles by Forkert, P.-G.

TOXICOLOGY

Bioactivation of 1,1-Dichloroethylene by CYP2E1 and CYP2F2 in Murine Lung

Department of Anatomy and Cell Biology (A.C.S., A.S, B.M., P.-G.F.), Queen's University, Kingston, Ontario, Canada; Laboratory of Pharmacology and Chemistry (B.I.G.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; and Department of Pharmacology and Toxicology (C.A.R., G.S.Y.), University of Utah, Salt Lake City, Utah

1,1-Dichloroethylene (DCE) exposure evokes lung toxicity with selective damage to bronchiolar Clara cells. Recent in vitro studies have implicated CYP2E1 and CYP2F2 in the bioactivation of DCE to 2-S-glutathionyl acetate [C], a putative conjugate of DCE epoxide with glutathione. An objective of this study was to test the hypothesis that bioactivation of DCE is catalyzed by both CYP2E1 and CYP2F2 in murine lung. Western blot analysis of lung microsomal proteins from DCE-treated CD-1 mice showed time-dependent loss of immunodetectable CYP2F2 and CYP2E1 protein. Dose-dependent formation of conjugate [C] was observed in the lungs of CD-1 mice treated with DCE (75–225 mg/kg), but it was not detected after pretreatment with 5-phenyl-1-pentyne (5-PIP). Treatment of mice with 5-PIP and also with diallyl sulfone (DASO₂) significantly inhibited hydroxylation of p-nitrophenol (PNP) and chlorzoxazone (CHZX). Incubation of recombinant CYP2F3 (a surrogate for CYP2F2) and recombinant CYP2E1 with PNP and CHZX confirmed that they are substrates for both of the recombinant enzymes. Incubation of the recombinant enzymes with DASO₂ or 5-PIP significantly inhibited hydroxylation of both PNP and CHZX. Bronchiolar injury was elicited in CD-1 mice treated with DCE (75 mg/kg), but it was abrogated with 5-PIP pretreatment. Bronchiolar toxicity also was manifested in the lungs of CYP2E1-null and wild-type mice treated with DCE (75 mg/kg), but protection ensued after pretreatment with 5-PIP or DASO₂. These results showed that bioactivation of DCE in murine lung occurred via the catalytic activities of both CYP2E1 and CYP2F2 and that bioactivation by these enzymes mediated the lung toxicity.

Address correspondence to: Dr. Poh-Gek Forkert, Department of Anatomy and Cell Biology, Queen's University, Kingston, ON, Canada K7L 3N6. E-mail: forkertp{at}post.queensu.ca

This article has been cited by other articles:

				L. G. Hernandez and P.-G. Forkert Inhibition of vinyl carbamate-induced mutagenicity and clastogenicity by the garlic constituent diallyl sulfone in F1 (Big Blue(R) x A/J) transgenic mice Carcinogenesis, August 1, 2007; 28(8): 1824 - 1830. [Abstract] [Full Text] [PDF]

				P.-G. Forkert, M. Kaufmann, G. Black, R. Bowers, H. Chen, K. Collins, A. Sharma, and G. Jones Oxidation of Vinyl Carbamate and Formation of 1,N6-Ethenodeoxyadenosine in Murine Lung Drug Metab. Dispos., May 1, 2007; 35(5): 713 - 720. [Abstract] [Full Text] [PDF]

				S. A. Gharib, W. C. Liles, G. Matute-Bello, R. W. Glenny, T. R. Martin, and W. A. Altemeier Computational Identification of Key Biological Modules and Transcription Factors in Acute Lung Injury Am. J. Respir. Crit. Care Med., March 15, 2006; 173(6): 653 - 658. [Abstract] [Full Text] [PDF]

				P.-G. Forkert, B. Millen, L. H. Lash, D. A. Putt, and B. I. Ghanayem Pulmonary Bronchiolar Cytotoxicity and Formation of Dichloroacetyl Lysine Protein Adducts in Mice Treated with Trichloroethylene J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 520 - 529. [Abstract] [Full Text] [PDF]

				H. Chang, L. W. Chang, Y.-H. Cheng, W.-T. Tsai, M.-X. Tsai, and P. Lin Preferential Induction of CYP1A1 and CYP1B1 in CCSP-Positive Cells Toxicol. Sci., January 1, 2006; 89(1): 205 - 213. [Abstract] [Full Text] [PDF]

				P.-G. Forkert, R. M. Baldwin, B. Millen, L. H. Lash, D. A. Putt, M. A. Shultz, and K. S. Collins PULMONARY BIOACTIVATION OF TRICHLOROETHYLENE TO CHLORAL HYDRATE: RELATIVE CONTRIBUTIONS OF CYP2E1, CYP2F, AND CYP2B1 Drug Metab. Dispos., October 1, 2005; 33(10): 1429 - 1437. [Abstract] [Full Text] [PDF]

				A. C. Simmonds, C. A. Reilly, R. M. Baldwin, B. I. Ghanayem, D. L. Lanza, G. S. Yost, K. S. Collins, and P.-G. Forkert BIOACTIVATION OF 1,1-DICHLOROETHYLENE TO ITS EPOXIDE BY CYP2E1 AND CYP2F ENZYMES Drug Metab. Dispos., September 1, 2004; 32(9): 1032 - 1039. [Abstract] [Full Text] [PDF]