Resistance of murine lung tumors to xenobiotic-induced cytotoxicity.
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 beta-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.
Forkert
P G
PG
Department of Anatomy, Queen's University, Kingston, Ontario, Canada.
Parkinson
A
A
Thaete
L G
LG
Malkinson
A M
AM
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004000:Dichloroethylenes / Q000633:toxicity; D004351:Drug Resistance; D015151:Immunoblotting; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000473:pathology*; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D009281:Naphthalenes / Q000633:toxicity; D010269:Paraquat / Q000633:toxicity; D015262:Xenobiotics / Q000633:toxicity*
D004000:Dichloroethylenes; D009281:Naphthalenes; D015262:Xenobiotics; C031721:naphthalene; C029297:vinylidene chloride; D003577:Cytochrome P-450 Enzyme System; D010269:Paraquat