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Increased Activity of Low-K_m Cyclic Adenosine 3':5'-Monophosphate Phosphodiesterase in Plasma Membranes of Morris Hepatoma 5123tc (h)¹

Department of Pharmacology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N OWO

The total cyclic adenosine 3':5'-monophosphate (cAMP) phosphodiesterase activities as well as the activities of the low- and high-K_m enzyme forms were investigated in homogenates, 100,000 x g supernatants, and plasma membrane fractions of rat liver and Morris hepatoma 5123tc (h); the responsiveness of hepatoma and liver plasma membrane (low-K_m) phosphodiesterases to imidazole (40 mM) and theophylline (5 mM) were also compared at cAMP concentrations of 1 and 7.5 µM.

The total cAMP phosphodiesterase activities of tumor homogenates and 100,000 x g supernatant fractions were found to be less than one-half those of liver; kinetic studies of homogenates indicated that this finding was largely due to a substantial reduction (53%) in activity of the hepatoma high-K_m enzyme.

In contrast, low-K_m cAMP phosphodiesterase activities for tumor homogenate and plasma membrane fractions were significantly (50%) higher than liver; this was particularly evident when cAMP concentrations were between 0.5 and 2 µM. Since these concentrations are in the range of basal physiological levels of cAMP in hepatocytes, the present results suggest that the reduced levels of cAMP, previously observed in hepatoma 5123tc (h), are primarily due to an increased rate of cAMP metabolism by low-K_m cAMP phosphodiesterase in plasma membranes of the tumor.

Imidazole increased the activity of the low-K_m cAMP phosphodiesterase of liver plasma membranes by 22 (1 µM cAMP) and 38% (7.5 µM cAMP); tumor activity was enhanced 35 and 50%, respectively, at 1 and 7.5 µM cAMP. Theophylline inhibited the plasma membrane phosphodiesterase activity of liver 79 and 53% at cAMP concentrations of 1 and 7.5 µM, respectively; hepatoma activity was inhibited 82 (1 µM cAMP) and 62% (7.5 µM cAMP).

¹ This work was supported by the Medical Research Council of Canada, Grant MA-4476.

Received 6/18/74. Accepted 11/13/74.