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Cyclic Adenosine 3',5'-Monophosphate Phosphodiesterase Activity in Normal, Differentiating, Regenerating, and Neoplastic Liver

Department of Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana 46202 [J. F. C., G. W.], and Department of Biochemistry, Howard University College of Medicine, Washington, D. C. 20001 [H. P. M.]

The behavior of cyclic 3',5'-nucleotide phosphodiesterases [cyclic adenosine 3',5'-monophosphate (cAMP) phosphodiesterases] was compared in normal resting liver, proliferating normal liver (from both developing and partially hepatectomized rats), and neoplastic liver (from both slowly and rapidly growing hepatomas). The enzyme activity was determined in the 100,000 x g supernant fluid at 1 mM cAMP (saturating substrate concentration, "high-K_m enzyme") and at 1 µM cAMP (near physiological substrate level, "low-K_m enzyme").

The pH curves for liver and the rapidly growing hepatoma 3924A were similar, namely, between pH 6.0 and 9.0. The results of kinetic studies and enzyme assays at 2 cAMP concentrations suggest, but do not yet prove rigorously, that there are present in normal, newborn, and regenerating liver, and in the hepatomas, two cAMP phosphodiesterases, one with a low apparent K_m of 2 to 3 µM for cAMP and another with an apparent K_m of 100 to 600 µM.

The high-K_m phosphodiesterase activity was decreased, in the average cell of the slowly growing hepatoma 47C and the rapidly growing hepatoma 3924A, to 58 and 13%, respectively, of the values of control normal livers. The low-K_m phosphodiesterase activity in slowly and rapidly growing hepatomas increased to 185 and 265%, respectively. This alteration in the isozyme pattern of cAMP phosphodiesterase appears to be specific to the neoplastic process, inasmuch as no similar pattern was observed in the rapidly growing differentiating or regenerating liver. The behavior of cAMP phosphodiesterase is in line with the change in pattern observed for the hexokinase and pyruvate kinase systems, and the observations support the view that neoplastic transformation entails a progressive emergence of a reprogramming of gene expression that appears to be linked with tumor growth rate.

¹ Recipient of American Cancer Society Institutional Grant IN-46-L.

² Recipient of USPHS Grant CA-10792.

³ Recipient of USPHS Grant CA-05034 and grants from the American Cancer Society and Damon Runyon Memorial Fund, Inc.

Received 6/30/72. Accepted 10/23/72.