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