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Resistance of Murine Lung Tumors to Xenobiotic-induced Cytotoxicity¹

Andrew Parkinson

Larry G. Thaete and Alvin M. Malkinson

Departments of Anatomy and Medicine, Queen's University, Kingston, Ontario, Canada K7L 3N6 [P. G. F.]; Department of Pharmacology, Toxicology and Therapeutics, Center of Environmental Health and Occupational Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160-7417 [A. P.]; and Molecular Toxicology and Environmental Health Sciences Program, School of Pharmacy, University of Colorado, Boulder, Colorado 80309 [L. G. T., A. M. M.]

² To whom requests for reprints should be addressed, at Department of Anatomy, Queen's University, Kingston, Ontario, Canada K7L 3N6.

Studies were performed to test the hypothesis that urethane-induced murine lung tumors exhibit xenobiotic resistance and alterations in pulmonary cytochrome P-450 enzymes. 1,1-Dichloroethylene, naphthalene, and paraquat were administered to tumor-bearing and control mice to elicit acute lung cytotoxicity, and responses were evaluated in tumors (papillary and solid), uninvolved surrounding tissue, and untreated control lung. 1,1-Dichloroethylene (125 mg/kg, i.p.) and naphthalene (225 mg/kg, i.p.) caused preferential necrosis of Clara cells in control lungs and uninvolved tissue of tumor-bearing lungs. In contrast, papillary and solid tumors were both resistant to 1,1-dichloroethylene-induced cytotoxicity. Paraquat (10, 20 mg/kg, i.v.) elicited Clara cell damage in control lungs and uninvolved lung tissue of tumor-bearing mice, with minor disruption of the alveolar epithelium. Neither papillary nor solid tumors sustained any apparent cell damage from paraquat. Immunoblots of P-450 enzymes confirmed constitutive expression of CYP2B1 in control lung and uninvolved lung tissue of tumor-bearing mice, but this P-450 enzyme was not detected in either adenomas or carcinomas. Lung CYP1A1 was inducible by β-naphthoflavone in non-tumor-bearing mice and uninvolved tissue of tumor-bearing mice; however, inducibility was decreased in adenomas and abolished in carcinomas. These results demonstrate resistance of lung tumor cells to chemically induced cytotoxicity and diminished expression of cytochrome P-450 enzymes in tumors.

¹ This work was supported by the Ontario Thoracic Society and Medical Research Council of Canada Grant MT-11769 (P. G. F.). P. G. F. is a Research Career Scientist, Ontario Ministry of Health, Health Research Personnel Development Program.

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 5/ 6/92. Accepted 10/ 1/92.

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