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Main Drug- and Carcinogen-metabolizing Enzyme Systems in Human Non-Small Cell Lung Cancer and Peritumoral Tissues¹

Département de Pharmacotoxicologie et Pharmacogénétique, Institut Gustave-Roussy (INSERM U 140 and CNRS URA 147), 94805 Villejuif Cedex [C. T., N. A., L. M., O. P., J. M., A. G., G. G. C.]; , and Centre Médico-chimrugical de la porte de Choisy [D. G.], 75013, Paris, France

² To whom requests for reprints should be addressed, at Institut Gustave-Roussy, Pavilion de recherche 2, 94805 Villejuif Cedex, France.

To better understand the importance of drug-metabolizing enzymes in carcinogenesis and anticancer drug sensitivity of human non-small cell lung cancer, we studied the main drug-metabolizing enzyme systems in both lung tumors and their corresponding nontumoral lung tissues in 12 patients. The following enzymes were assayed by Western blot analysis: cytochromes P-450 (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4); epoxide hydrolase; and glutathione S-transferase isoenzymes (GST-, -µ, and -<). The activity of the following enzymes or cofactor were determined by spectrophotometric or fluorometric assays: glutathione 5-transferase (GST); total glutathione; UDP-glucuronosyltransferase; β-glucuronidase; sulfotransferase; and sulfatase.

Results showed the presence of cytochrome P-450 1A1/1A2 in both tumoral and nontumoral tissues. P-450 1A1/1A2 levels were 3-fold lower in tumors compared to corresponding nontumoral tissues (P < 0.05). None of the other probed cytochromes P-450 were detected in either tumoral or nontumoral lung tissues. For the glutathione system, no significant difference between tumoral and nontumoral tissues was observed (GST activity, glutathione content, GST-, -µ, and -<). A positive linear correlation was observed between GST activity and GST- or GST-<. No significant difference was observed for the glucuronide and the sulfate pathways and their corresponding hydrolytic enzymes. Epoxide hydrolase was significantly decreased in tumors compared to nontumoral lung tissues (P < 0.05).

In conclusion, these results showed differences between non-small cell lung tumors and nontumoral tissues for cytochrome P-450 1A1/1A2 and epoxide hydrolase. These differences between tumors and peritumoral tissues with regard to these drug-metabolizing enzymes could reflect differences occurring after malignant transformation and may play a role in drug sensitivity to anticancer drugs.

¹ This work was supported by the Fondation pour la Recherche Médicale, the Institut National de la Santé et de la Recherche Médicale (INSERM), and the Centre National de la Recherche Scientifique (CNRS).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/31/93. Accepted 7/23/93.

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