Molecular Pharmacology, Vol 12, 195-202, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Changes in Catecholamine- and Glucagon-Responsive Adenylate Cyclase Activity in Preneoplastic Rat Liver

¹ Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria 3084, Australia

Increases in basal and catecholamine-responsive adenylate cyclase activity have been observed in livers of rats treated with the carcinogen 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB). These increases are accompanied by a decrease in glucagon responsiveness of the enzyme. Binding of 3'-MeDAB metabolites reaches a peak at 3 weeks, considerably earlier than the peak increases in adenylate cyclase activity at 6 weeks. By the time tumors are detected in the tissue (10-20 weeks), adenylate cyclase activity and response to catecholamine stimulation are back to or below normal. The greatly increased stimulation of adenylate cyclase activity by catecholamines is a beta receptor effect; however, inhibition of the enzyme by catecholamines is also seen when there is elevated basal activity and may be an alpha adrenergic effect. That glucagon and catecholamine effects are additive at certain concentrations of catecholamine, but only partially so at others, indicates that the two receptor-cyclase systems are not entirely separate. The preneoplastic rat liver would appear to be a suitable tissue to study hormone-receptor interactions at both molecular and physiological levels. It is the first broken cell preparation in which inhibitory effects of catecholamines on adenylate cyclase activity have been observed. The relationship between the observed changes and the induction of cancer is not yet clear.

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ACKNOWLEDGMENTS We gratefully acknowledge the technical help of Gerard Laumen, comments on the manuscript by Lincoln T. Potter, and the gift of glucagon from Ciba.