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N-NITROSODIETHYLAMINE AND 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE INDUCED MORPHOLOGICAL TRANSFORMATION OF CH3/10T1/2CL8 CELLS EXPRESSING HUMAN CYTOCHROME P450 2A6
Citation:
Nesnow, S., S. Beck, S. Rosenblum, J. Lasley, H. Tiano, M. Hosokawa, AND R. Langenbach. N-NITROSODIETHYLAMINE AND 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE INDUCED MORPHOLOGICAL TRANSFORMATION OF CH3/10T1/2CL8 CELLS EXPRESSING HUMAN CYTOCHROME P450 2A6. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-94/417.
Description:
Transfection of specific genes into cells capable of expressing chemically-induced morphological cell transformation provides a valuable approach to study the mechanisms of action of carcinogens. uman cytochrome P450 isozyme, CYP2A6, has been successfully expressed from a retroviral vector in transformable C3H/1OT1/2 (1OT1/2) mouse embryo fibroblasts and these resulting 10T1/2 clones were evaluated for the cytotoxic and transforming activities of two nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosodiethylamine (DEN). 10T1/2-clone 29 cells, which expressed high levels of CYP2A6 activity, were responsive to the cytotoxic and morphological transforming effects of DEN or NNK on a concentration-related basis. n 10T1/2-clone 29 cells, DEN at 600 ug/ml decreased cell survival to 67%, and induced 0.5 Type II&III foci/dish. NK at 400 ug/ml administered to 10T1/2-clone 29 cells decreased survival to 57% and induced 0.43 Type II&III foci/dish. ild-type 10TI/2 cells and 10T1/2-clone 4 cells (infected with the vector but not expressing the CYP2A6 activity] were unresponsive. hese results indicate that expression of a CDNA coding for cytochrome P450 in 10T1/2 cells can provide information about the role of the enzyme in the activities of chemical carcinogens and also increase the sensitivity of 10T1/2 cells to a larger number of classes of chemical carcinogens.