The effect of the phorbol ester tumor promoters on the basal and catecholamine-stimulated levels of cyclic adenosine 3':5'-monophosphate in mouse skin and epidermis in vivo

To measure the in vivo levels of cyclic adenosine 3':5'-monophosphate (cyclic AMP) in mouse skin, precautions must be taken to avoid artifactual alterations after excision of the skin from the mouse. With such precautions, the level of cyclic AMP in mouse epidermal-dermal preparations was unchanged 1 to 18 hr after application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse skin. The accumulation of cyclic AMP in response to isoproterenol or the naturally occurring catecholamine epinephrine was, however, significantly diminished 9 to 24 hr after application of TPA. No enhanced accumulation of cyclic AMP in response to alpha-adrenergic stimulation accompanied this diminished beta-adrenergic responsiveness. Experiments with pure epidermis confirmed that these observations reflected the effects of TPA on the epidermal cells in the epidermal-dermal preparations. The metabolism of isoproterenol in TPA-treated epidermis was the same as that in control epidermis. Finally, the tumor-promoting activity of various doses of TPA and of other phorbol esters correlated with their ability to diminish the beta-adrenergic responsiveness of the epidermis.