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Vol. 289, Issue 2, 641-648, May 1999

Cytochrome P-450-Dependent Bioactivation of 1,1-Dichloroethylene to a Reactive Epoxide in Human Lung and Liver Microsomes1

Taylor F. Dowsley, Ken Reid, Dimitri Petsikas, Judith B. Ulreich, Robyn L. Fisher and Poh-Gek Forkert

Departments of Anatomy and Cell Biology (T.F.D., P.G.F.) and Surgery (K.R., D.P.), Queen's University, Kingston, Ontario, Canada; Department of Surgery, University of Arizona, Tucson, Arizona (J.B.U.); and Vitron, Inc., Tucson, Arizona (R.B.L.)

We investigated the cytochrome P-450-dependent metabolism of 1,1-dichloroethylene (DCE) by human lung and liver microsomes and compared the results from analogous experiments in mice. Metabolites were identified by HPLC analysis of their glutathione conjugates and/or hydrolyzed products and were detected by using [14C]DCE. The role of human CYP2E1 in the metabolic reactions was examined by comparing p-nitrophenol hydroxylase activities with levels of metabolites formed and by using the CYP2E1-selective inhibitor diallyl sulfone. The major products formed in microsomal incubations containing NADPH were the DCE-epoxide-derived glutathione conjugates 2-(S-glutathionyl)acetyl glutathione and 2-S-glutathionyl acetate. Lower levels of the acetal of 2,2-dichloroacetaldehyde were also detected. In lung samples from eight patients, the amounts of epoxide-derived conjugates formed ranged from 15.6 ± 4.23 to 34.9 ± 12.75 pmol/mg protein/min. The levels in murine lung were higher at 40.0 ± 3.8 pmol/mg protein/min. In liver samples from five patients, conjugate levels ranged from 46.5 ± 8.3 to 240.0 ± 10.5 pmol/mg protein/min, whereas levels in murine liver were 83.0 ± 6.2 pmol/mg protein/min. Conjugate levels formed in human liver correlated with the relative levels of p-nitrophenol hydroxylase activity present, but this relationship was equivocal in human lung. Diallyl sulfone inhibited the formation of the glutathione conjugates (20-65%) in liver samples from all four patients, whereas only one of five human lung samples exhibited this inhibition (27%). These results demonstrated that the DCE-epoxide is a major metabolite formed by human microsomes and is mediated by CYP2E1 in liver and in some individuals in lung.

0022-3565/99/2892-0641$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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