The action of mitomycin C on the induction of cyclic AMP phosphodiesterase and the development of desensitization of adenylate cyclase by isoproterenol in rat ascites hepatoma AH130 cells.

The treatment of AH130 cells with isoproterenol (IPN) resulted in an increase in the activity of cyclic adenosine 3':5'-monophosphate (cyclic AMP) phosphodiesterase with a low Km value and a decrease in IPN-stimulated activity of adenylate cyclase. The activity of cyclic AMP phosphodiesterase was increased by IPN in a dose-dependent manner and reached a maximal increase at 30 min after the addition of 10(-4)M IPN. The addition of mitomycin C (MMC) at 15 min after the initiation of the treatment with IPN inhibited the increase in the activity of cyclic AMP phosphodiesterase in a dose-dependent manner. The extent of the development of desensitization, which was observed as a decrease in IPN-stimulated activity of adenylate cyclase, was dependent on the treatment time with IPN and the concentration of IPN. Desensitization was also observed as a decrease in prostaglandin E1-stimulated activity but not in basal and NaF-stimulated activity. The combined treatment with IPN and MMC showed a higher IPN-stimulated activity of adenylate cyclase than with a single treatment with IPN. This effect resulted from the enhancement of IPN-stimulated activity of the enzyme by MMC itself. These results show that the treatment of AH130 cells with IPN caused an induction of cyclic AMP phosphodiesterase and the development of desensitization of adenylate cyclase. Since the combined treatment with MMC inhibited both phenomena, the high intracellular cyclic AMP level appeared to be maintained by the combined treatment for a longer term than by a single treatment with IPN.