EFFECT OF PHORBOL ESTER TUMOR PROMOTERS ON BASAL AND CATECHOLAMINE-STIMULATED LEVELS OF CYCLIC ADENOSINE 3'-5'-MONOPHOSPHATE IN MOUSE SKIN AND EPIDERMIS INVIVO
To measure in vivo levels of cyclic[c]AMP in mouse skin, precautions must be taken to avoid artifactual alterations after excision of skin from the mouse. With such precautions, the level of cAMP in mouse epidermal-dermal preparations was unchanged 1-18 h after application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse skin. The accumulation of cAMP in response to isoproterenol or the naturally occurring catecholamine epinephrine was significantly diminished 9-24 h after application of TPA. No enhanced accumulation of cAMP 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 epidermal cells in epidermal-dermal preparations. The metabolism of isoproterenol in TPA treated epidermis was the same as that in control epidermis. The tumor promoting activity of various doses of TPA and of other phorbol esters correlated with their ability to diminish .beta.-adrenergic responsiveness of the epidermis.