Pulmonary Bioactivation of 1,1-Dichloroethylene Is Associated with CYP2E1 Levels in A/J, CD-1, and C57BL/6 Mice

1,1-Dichloroethylene (DCE) elicits lung cytotoxicity and selectively targets Clara cells of bronchioles. The toxic effects are ascribed to CYP2E1-mediated formation of reactive intermediates including the DCE epoxide. Here we tested the hypothesis that differential CYP2E1 levels in the lungs of A/J,...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2001-06, Vol.297 (3), p.1193
Main Authors: Forkert, P G, Boyd, S M, Ulreich, J B
Format: Article
Language:English
Subjects:
Animals
Biotransformation - drug effects
Carbon Radioisotopes
Chromatography, High Pressure Liquid
Cytochrome P-450 CYP2E1 - analysis
Cytochrome P-450 CYP2E1 - metabolism
Cytosol - chemistry
Cytosol - metabolism
Dichloroethylenes - administration & dosage
Dichloroethylenes - metabolism
Epoxy Compounds - metabolism
Female
Glutathione - analogs & derivatives
Glutathione - analysis
Glutathione - biosynthesis
Glutathione - metabolism
Immunohistochemistry
Injections, Intraperitoneal
Lung - cytology
Lung - drug effects
Lung - metabolism
Mice
Mice, Inbred A
Mice, Inbred C57BL
Radioligand Assay
Species Specificity
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:1,1-Dichloroethylene (DCE) elicits lung cytotoxicity and selectively targets Clara cells of bronchioles. The toxic effects are ascribed to CYP2E1-mediated formation of reactive intermediates including the DCE epoxide. Here we tested the hypothesis that differential CYP2E1 levels in the lungs of A/J, CD-1, and C57BL/6 mice lead to differences in the extents of DCE bioactivation and lung damage. Our results showed that lung CYP2E1 levels differed significantly in the three murine strains, and followed the rank order A/J > CD-1 > C57BL/6. Covalent binding of [ 14 C]DCE to lung proteins in A/J mice was significantly higher than in either CD-1 or C57BL/6 mice. HPLC analysis of lung cytosol from DCE-treated mice showed that 2- S -glutathionyl acetate, a glutathione (GSH) conjugate derived from the epoxide (conjugate [C]), was the major metabolite formed. Levels of [C] detected in cytosol from A/J and CD-1 mice were significantly higher than in C57BL/6 mice. Immunohistochemical staining for [C] was pronounced in the lungs of A/J mice, was lower in CD-1 mice, and was lowest in C57BL/6 mice. Levels of GSH were similar in the lungs of all untreated mice. However, significant reduction in GSH was found in DCE-treated mice, with decreases comparable in all three strains. Bronchiolar Clara cell damage was more severe in A/J and CD-1 mice than in C57BL/6 mice. These results showed differences in CYP2E1 levels in the lungs of A/J, CD-1, and C57BL/6 mice that correlated with the extent to which the DCE epoxide is formed as well as with the severity of lung cytotoxicity.
ISSN:0022-3565
1521-0103