The ability of N6, O2'-dibutyryl cyclic AMP (DBcAMP) to regulate a number of metabolic events in four lines of cultured rat hepatomas has been examined. Although dexamethasone induces tyrosine transaminase in all four lines, DBcAMP induces this enzyme normally only in H35 cells. A slight increase in transaminase activity was seen with MH1C1 cells and HTC cells, but no effect was detectable in RLC cells. In contrast, phosphoenolpyruvate carboxykinase activity is increased by both agents in H35 and MH1C1 cells, but neither had any effect in HTC or RLC cells.

DBcAMP caused a rapid inhibition of the growth rate and DNA synthesis and an increase in protein content in both H35 and MH1C1 cells but not in HTC or RLC cells. The effect of DBcAMP on DNA synthesis in MH1C1 cells could be reversed by deoxycytidine as is also the case with H35 cells.

The resistance of HTC and RLC cells to DBcAMP was not due to reduced uptake or deacylation as judged by studies with [3H]DBcAMP. The cyclic nucleotide appears to enter the cells by passive diffusion as the intracellular concentration approaches that in the medium within 30–60 min. Possible explanations for the differential responses observed are discussed.

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