ALTERATIONS IN EXPRESSION OF CYP1A1 AND NADPH-CYTOCHROME P450 REDUCTASE DURING LUNG-TUMOR DEVELOPMENT IN SWR J MICE/

We investigated the expression of the cytochrome P450 isozyme, CYP1A1, during the course of tumor development and examined the distribution of the CYP1A1 protein in hyperplastic foci, adenomas and carcinomas, T he expression of NADPH-cytochrome P450 reductase, a flavoprotein that mediates the reduction of cytochrome P450, was also determined, Mice w ere administered urethane (1 mg/g body wt) and were killed at 10, 22 a nd 52 weeks to coincide with the time at which hyperplastic foci, aden omas and carcinomas were established, respectively, Protein immunoblot ting revealed that the antibody for CYP1A1 detected a protein band of similar to M(r) 56 000 in microsomes from mice treated with beta-napht hoflavone, The antibody for NADPH-cytochrome P450 reductase detected a protein band of similar to M(r) 79 000 in microsomes from control mic e and mice treated with beta-naphthoflavone, Immunohistochemical studi es showed that CYP1A1 was not detected constitutively in the lungs of both non-tumor- and tumor-bearing mice, Treatment with beta-naphthofla vone evoked high induction of CYP1A1 in morphologically normal tissues of all mice, with localization of the protein mainly in endothelial a nd alveolar type II cells, In contrast, inducibility of CYP1A1 by beta -naphthoflavone was markedly reduced in early hyperplastic foci seen 1 0 weeks after urethane exposure. At 22 weeks, CYP1A1 was found at low levels in both solid and papillary tumors, whereas at 52 weeks, lung c arcinomas were devoid of expression of this protein, However, CYP1A1 i nducibility was highly expressed in late hyperplastic foci manifested at 52 weeks, NADPH-cytochrome P450 reductase was expressed in morpholo gically normal lung tissue of all mice under control conditions and af ter treatment with beta-naphthoflavone, and was localized mainly in Cl ara and alveolar type II cells, In contrast, reductase expression in a il tumor sites was diminished and closely paralleled that of CYP1A1, T hese results demonstrated progressive depression of induced CYP1A1 and reductase expression in early hyperplasias, adenomas and carcinomas, suggesting that the co-ordinate regulation of both enzymes is highly c onserved during tumor development, Furthemore, these findings suggeste d diminished capabilities for metabolic activation of potential toxica nts and/or carcinogens after neoplastic transformation.