Journal Article

Alterations in expression of CYPlA1 and NADPH-cytochrome P450 reductase during lung tumor development in SWR/J mice

Poh-Gek Forkert, Jason A. Lord and Andrew Parkinson

in Carcinogenesis

Volume 17, issue 1, pages 127-132
Published in print January 1996 | ISSN: 0143-3334
e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.1.127
Alterations in expression of CYPlA1 and NADPH-cytochrome P450 reductase during lung tumor development in SWR/J mice

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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. The expression of NADPH-cytochrome P450 reductase, a flavoprotein that mediates the reduction of cytochrome P450, was also determined. Mice were administered urethane (1 mg/g body wt) and were killed at 10, 22 and 52 weeks to coincide with the time at which hyperplastic foci, adenomas and carcinomas were established, respectively. Protein immuno-blotting revealed that the antibody for CYP1A1 detected a protein band of ˜Mr 56 000 in microsomes from mice treated with βP-naphthoflavone. The antibody for NADPH-cytochrome P450 reductase detected a protein band of ∼Mr 79 000 in microsomes from control mice and mice treated with βP-naphthoflavone. Immunohistochemical studies showed that CYP1A1 was not detected constitutively in the lungs of both non-tumor-and tumor-bearing mice. Treatment with βP-napthoflavone evoked high induction of CYP1A1 in morphologically normal tissues of all mice, with localization of the protein mainly in endothelial and alveolar type II cells. In contrast, inducibility of CYP1A1 by βP-naphthoflavone was markedly reduced in early hyperplastic foci seen 10 weeks after urthane exposure. At 22 weeks, CYP1A1 was found at low levels in both solid and papillary tumors, whereas at 52 weeks, lung carcinomas were devoid of expression of this protein. However, CYP1A1 inducibility was highly expressed in late hyperplastic focimanifested at 52 weeks. NADPH-cytochrome P450 reductase was expressed in morphologically normal lung tissue of all mice under control conditions and after treatment with βP-naphthoflavone, and was localized mainly in Clara and alveolar type II cells. In contrast, reductase expression in all tumor sites was diminished and closely paralleled that of CYP1A1. These 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 conserved during tumor development. Furthemore, these findings suggested diminished capabilities for metabolic activation of potential toxicants and/or carcinogens after neoplastic transformation.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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