This study investigates the potential of
urethane-induced lung
tumors to activate
1,1-dichloroethylene (
DCE), a chemical that causes Clara cell damage in mice. Metabolism of DCE is catalyzed by the
cytochrome P450 isozyme CYP2E1 to the DCE-
epoxide, as assessed by formation of
2-S-glutathionyl acetate (GTA), the
glutathione (GSH)-conjugated product of the
epoxide. Immunohistochemical studies were performed in normal non-
tumor- and
tumor-bearing mice to determine lung cells that contained
CYP2E1 available for DCE metabolism. The site of GTA formation was also determined. The results showed that most of the
CYP2E1 were expressed in Clara cells from normal lung and in uninvolved tissue of
tumor-bearing lung. In contrast,
CYP2E1 was minimally expressed in neoplastic tissue, including
hyperplasias,
adenomas, and
carcinomas. Parallel studies of adjacent lung sections revealed that GTA immunostaining was most intense in Clara cells of normal lung tissue and in uninvolved tissue of
tumor-bearing lungs from DCE-treated mice. However, GTA staining was negligible at all
tumor sites. These results demonstrated that the cellular sites where
CYP2E1 was expressed were the same as those in which the GTA metabolite was identified. They further showed that expression of both
CYP2E1 and GTA was markedly reduced in
hyperplasias,
adenomas, and
carcinomas. These observations suggest that these tissue types are defective in their capability for bioactivation of DCE.