IMMUNOHISTOCHEMICAL DETECTION OF CYP2E1 AND 2-S-GLUTATHIONYL ACETATE IN MURINE LUNG-TUMORS - DIMINISHED FORMATION OF REACTIVE INTERMEDIATESOF 1,1-DICHLOROETHYLENE

This study investigates the potential of urethane-induced lung tumors to activate 1,1-dichloroethylene (DCE), a chemical that causes Clara c ell damage in mice. Metabolism of DCE is catalyzed by the cytochrome P 450 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 mere performed in normal n on-tumor- and tumor-bearing mice to determine lung cells that containe d CYP2E1 available for DCE metabolism. The site of GTA formation was a lso determined. The results showed that most of the CYP2E1 were expres sed in Clara cells from normal lung and in uninvolved tissue of tumor- bearing lung. In contrast, CYP2E1 was minimally expressed in neoplasti c tissue, including hyperplasias, adenomas, and carcinomas. Parallel s tudies of adjacent lung sections revealed that GTA immunostaining was most intense in Clara cells of normal lung tissue and in uninvolved ti ssue of tumor-bearing lungs from DCE-treated mice. However, GTA staini ng was negligible at all tumor sites. These results demonstrated that the cellular sites where CYP2E1 Leas expressed were the same as those in which the GTA metabolite was identified. They further showed that e xpression of both CYP2E1 and GTA was markedly reduced in hyperplasias, adenomas, and carcinomas. These observations suggest that these tissu e types are defective in their capability for bioactivation of DCE.