Differential effect of 5-bromodeoxyuridine on the concentrations of specific enzymes in hepatoma cells in culture.

Growth of cultured rat hepatoma cells in the presence of 5-bromodeoxyuridine results in a rapid inhibition of the synthesis of adrenal steroid-inducible tyrosine aminotransferase (EC 2.6.1.5) and slower decreases in the concentrations of lactate dehydrogenase (EC 1.1.1.27), alcohol dehydrogenase (EC.1.1.1.1), and glucose-6-phosphate dehydrogenase (EC 1.1.1.49). During the same period, neither overall cell growth nor the concentrations of malate dehydrogenase (EC 1.1.1.37), acid phosphatase (EC 3.1.3.2), or alanine aminotransferase (EC 2.6.1.2) were significantly decreased by the base analog. Addition of thymidine to the growth medium rapidly counteracts the inhibition of tyrosine aminotransferase synthesis but restores the normal concentrations of lactate-, alcohol-, and glucose-6-phosphate dehydrogenases much more slowly. Growth of the cells for only one generation in the presence of bromodeoxyuridine, followed by the addition of thymidine, produces transient decreases in the concentrations of the three "late-responding" dehydrogenases, beginning 2-3 generations after exposure to the analog.It is concluded that the selective inhibitory effects of the analog could result from a mechanism in which bromodeoxyuridine is uniformly incorporated into cellular DNA, but inhibits the transcription of only certain genes into messenger RNA. A mathematical model is derived to account for the observed differences in the kinetics of the inhibition of synthesis of the gene products that are sensitive to the analog.