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.