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Modulation of the Cell Cycle of Cultured Mouse Liver Cells by Benzo(a)pyrene and Its Derivatives¹

Laboratory of Chemical Biodynamics, Lawrence Berkeley Laboratory, University of California, Berkeley, California 94720

We have used flow cytometry to monitor the alterations in cell cycle distributions caused by chemical carcinogens. Two closely derived mouse liver cell strains growing in culture have been studied with regard to the effect of benzo(a)-pyrene and derivatives of benzo(a)pyrene on DNA synthesis. The derivatives tested were (±)-trans-7,8ß-dihydroxy-7,8-dihydrobenzo(a)pyrene; (±)-7,8ß-dihydroxy-9ß, 10ß-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol-epoxide); and 7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene. One cell strain used in this study, NMuLi clone 7, is not highly inducible for the enzyme system (aryl hydrocarbon monooxygenase) that converts the parent compound into the derivatives listed above. The second strain, NMuLi clone 8, is highly inducible for aryl hydrocarbon monooxygenase. Correlated with the high level of metabolic activity is an increased sensitivity to the cytotoxicity of the parent compound. However, both strains were equally sensitive to the diol-epoxide. Flow cytometry analysis and measurements of [³H]thymidine incorporation into DNA showed that the diol-epoxide increased the number of cells involved in DNA synthesis but that the rate of DNA synthesis was greatly reduced. Benzo(a)pyrene and ±(trans)-7,8ß-dihydroxy-7,8-dihydrobenzo(a)pyrene had this same effect on NMuLi clone 8 but not on NMuLi clone 7. The perturbations caused by diol-epoxide took place within one cell cycle, and the cell did not traverse a second cycle. Kinetic modeling studies indicated that the cell cycle perturbations caused by diol-epoxide are consistent, with the rate of traverse of S being slower than other phases of the cell cycle, and that as cells move through S their rate of DNA synthesis decreases.

¹ Work carried out under the auspices of the Division of Biomedical and Environmental Research, United States Department of Energy.

² To whom requests for reprints should be addressed.

³ Present address: Technicon Instruments Corp., 511 Benedict Avenue, Tarrytown, N. Y. 10591.

⁴ Present address: LAC University of Southern California Cancer Center, 1721 North Griffin Avenue, Los Angeles, Calif. 90031.

Received 12/27/78. Accepted 4/10/79.