The potent skin
tumor promoter (
12-O-tetradecanoyl phorbol-13-acetate (TPA) stimulates epidermal macromolecular synthesis as well as proliferation, but little is known of specific functional aberrations produced by TPA. This report presents results of a study on the effects of TPA on epidermal
histidase (
L-histidine ammonia lyase), an
enzyme found in normal epidermis but not in dermis or in mouse
squamous cell carcinomas.
Histidase activity was assayed on postmitochondrial supernatants obtained from hairless mouse epidermis after removal by keratotome. Topical TPA treatment at doses active in
tumor promotion (1.7 to 17.0 nmoles/application) produced dose-dependent decreases in epidermal
histidase specific activity at 19 hr posttreatment. The onset of the decrease occurred at 12 hr with recovery to control level specific activity by 5 days, showing kinetics similar to those obtained for stimulation of
DNA synthesis. This decrease in
histidase could not be attributed to a general inhibition of soluble
protein synthesis or to the appearance of an inhibitor of
histidase activity. The strong promoter TPA produced a greater
histidase decrease than did the moderate promoter and
mitogen 12,13-didecanoyl
phorbol at equimolar dose, while
phorbol, a nonpromoter and nonmitogen, produced no effects on
histidase. The relationship of this
histidase depression to
tumor promotion and not initiation is further indicated by the finding that (a)
Tween 60, a structurally unrelated
tumor promotor, also produced a decrease in
histidase; and (b) the
tumor initiator urethan and an initiating dose of 9,10-dimethybenz(a)
anthracene showed no effects on histadase activity.