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, 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.
Forkert
P G
PG
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada. forkertp@post.queensu.ca
Boyd
S M
SM
Ulreich
J B
JB
D000818:Animals; D001711:Biotransformation / Q000187:drug effects*; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D019392:Cytochrome P-450 CYP2E1 / Q000032:analysis / Q000378:metabolism*; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D004000:Dichloroethylenes / Q000008:administration & dosage / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives* / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D011869:Radioligand Assay; D013045:Species Specificity
C117291:2-S-glutathionyl acetate; D002250:Carbon Radioisotopes; D004000:Dichloroethylenes; D004852:Epoxy Compounds; C029297:vinylidene chloride; C117290:1,1-dichloroethylene epoxide; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione