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 metabo lism of DCE yields 2-S-glutathionyl acetate (conjugate [C]), a glutathione conjugate derived from DCE-epoxide, believed to be the ultimate toxic speci es. We used immunohistochemistry to investigate CYP2E1 expression in nontum or- and tumor-bearing lung to identify cells capable of generating [C]. CYP 2E1 and [C] were colocalized in adjacent tissue sections to determine coinc idence between CYPPE1 and [C] in lung cells. CYP2E1 was highly localized to the bronchiolar epithelium of nontumor-bearing lung and in uninvolved tiss ue of tumor-bearing lung and was concentrated in the Clara cells. in contra st, tumor foci including hyperplasias, adenomas, and carcinomas were defici ent in CYPPE1 in both untreated and DCE-treated mice. Immunoreactivity for [C] was also detected in the bronchiolar epithelium in nontumor-bearing lun g and uninvolved tissue of tumor-bearing lung of DCE-treated mice and was r educed in hyperplasias, adenomas, or carcinomas. Thus, there was a coincide nce between the sites of CYPPE1 expression and [C] formation. Conjugate [C] accumulated only in lung cells in which CYP2E1 was expressed. Histochemica l staining for glutathione confirmed its presence in tumor foci. Thus, bioa ctivation and conjugation of DCE occur in structurally normal tissue from b oth nontumor- and tumor-bearing lung but was lost in tumor tissue, irrespec tive of the stage of tumor development.