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Increased Guanylate Cyclase Activity and Guanosine 3',5'-Monophosphate Content in Ethionine-induced Hepatomas¹

Department of Medicine, Veterans Administration Hospital and University of Pittsburgh, Pittsburgh, Pennsylvania 15240

Ethionine-induced hepatomas are characterized by high adenylate cyclase activity and cyclic adenosine 3',5'-monophosphate content relative to those of surrounding liver or liver from pair-fed control rats. The present study examined the properties of the guanylate cyclase-cyclic guanosine 3',5'-monophosphate (cGMP) system of these tissues. cGMP levels of the ethionine-induced hepatomas, determined in both specimens quick-frozen in situ and after in vitro incubation of tissue slices, were approximately 2 times higher than those of surrounding liver or controls. Higher cGMP in the tumors was associated with an increase in whole homogenate, soluble, and particulate guanylate cyclase activities, as well as an increase in soluble cGMP-phosphodiesterase activity. 3-Isobutyl-1-methylxanthine, a potent inhibitor of cGMP-phosphodiesterase activity, potentiated the differences in cGMP between slices of the hepatomas and surrounding liver or control, suggesting that the higher steady-state cGMP content of the tumors reflected enhanced basal cGMP synthesis which was partially offset by increased nucleotide degradation. In the hepatomas, a greater proportion of the total guanylate cyclase activity was located in the particulate cell fraction 31%) as compared to the subcellular distribution of enzyme activity in either surrounding liver or controls (15% of total in the particulate fraction). Carbamylcholine, which increased cGMP 3-fold in surrounding liver and controls, ailed to alter cGMP levels in slices of hepatoma. Further, the relative changes in both cGMP accumulation and guanylate cyclase activity of the tumors in response to NaN₃, NH₂OH, and NaNO₂ were blunted compared to surrounding liver or controls, although in each instance a response was clearly evident. Ethionine-induced hepatomas are thus characterized by: (a) significant increases in cGMP content and in guanylate cyclase and cGMP-phosphodiesterase activities, (b) a change in the subcellular distribution of guanylate cyclase, and (c) altered responsiveness of the guanylate cyclase-cGMP system to several agonists.

¹ This study was supported by the Veterans Administration.

² Clinical Investigator of the Veterans Administration Hospital and recipient of American College of Physicians Teaching and Research Scholarship. To whom requests for reprints should be addressed.

Received 5/19/76. Accepted 10/ 6/76.