Modulation of the cell cycle of cultured mouse liver cells by benzo(a)pyrene and its derivatives.

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 cub lure have been studied with regard to the effect of benzo(a) pyrene and derivatives of benzo(a)pyrene on DNA synthe sis. The derivatives tested were (±)-trans-7a,8$-dihydroxy 7,8-dihydrobenzo(a)pyrene; (±)-7a,8$-dihydroxy-9$, 10/1epoxy-7,8,9,i 0-tetrahydrobenzo(a)pyrene (diol-epoxide); and 7 ,8 ,9 , 10-tetrahydroxy7,8,9, i 0-tetrahydrobenzo(a)pyrene. One cell strain used in this study, NMuLi clone 7, is not highly inducible for the enzyme system (aryl hydrocarbon monooxy genase) 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 sensi tivity to the cytotoxicity of the parent compound. However, both strains were equally sensitive to the diol-epoxide. Flow cyto metry analysis and measurements of [3Hjthymidine incorpora tion 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)-7a,8fl-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.