Diminished CYP2E1 expression and formation of 2-S-glutathionyl acetate, a glutathione conjugate derived from 1,1-dichloroethylene epoxide, in murine lung tumors.
We hypothesized that resistance of lung tumors to the cytotoxic effects of xenobiotics is associated with loss of cytochrome P-450 expression, leading to defective formation of reactive intermediates. To test this hypothesis, we investigated 1,1-dichloroethylene (DCE), a chemical that causes Clara cell damage, in a urethane-induced model of lung tumorigenesis. Lung metabolism of DCE yields 2-S-glutathionyl acetate (conjugate [C]), a glutathione conjugate derived from DCE-epoxide, believed to be the ultimate toxic species. We used immunohistochemistry to investigate CYP2E1 expression in nontumor- and tumor-bearing lung to identify cells capable of generating [C]. CYP2E1 and [C] were colocalized in adjacent tissue sections to determine coincidence between CYP2E1 and [C] in lung cells. CYP2E1 was highly localized to the bronchiolar epithelium of nontumor-bearing lung and in uninvolved tissue of tumor-bearing lung and was concentrated in the Clara cells. In contrast, tumor foci including hyperplasias, adenomas, and carcinomas were deficient in CYP2E1 in both untreated and DCE-treated mice. Immunoreactivity for [C] was also detected in the bronchiolar epithelium in nontumor-bearing lung and uninvolved tissue of tumor-bearing lung of DCE-treated mice and was reduced in hyperplasias, adenomas, or carcinomas. Thus, there was a coincidence between the sites of CYP2E1 expression and [C] formation. Conjugate [C] accumulated only in lung cells in which CYP2E1 was expressed. Histochemical staining for glutathione confirmed its presence in tumor foci. Thus, bioactivation and conjugation of DCE occur in structurally normal tissue from both nontumor- and tumor-bearing lung but was lost in tumor tissue, irrespective of the stage of tumor development.
Forkert
P G
PG
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada. forkertp@post.queensu.ca
Malkinson
A M
AM
Rice
P
P
Moussa
M
M
D000236:Adenoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002277:Carcinoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D004000:Dichloroethylenes / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism*; D006965:Hyperplasia / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice
C117291:2-S-glutathionyl acetate; D004000:Dichloroethylenes; D004852:Epoxy Compounds; C117290:1,1-dichloroethylene epoxide; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione