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Decrease of epidermal histidase activity by tumor-promoting phorbol esters
Abstract:
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.
Insights
The skin tumor promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA) significantly decreases epidermal histidase activity in mice. This effect is linked to tumor promotion, not initiation, and is observed with other promoters like Tween 60.
Area of Science:
- Dermatology
- Biochemistry
- Carcinogenesis
Background:
- 12-O-tetradecanoyl phorbol-13-acetate (TPA) is a potent skin tumor promoter.
- Specific functional changes induced by TPA in epidermal cells are not well understood.
- Epidermal histidase (L-histidine ammonia lyase) is present in normal epidermis but absent in squamous cell carcinomas.
Purpose of the Study:
- To investigate the effects of TPA on epidermal histidase activity.
- To determine if changes in histidase activity correlate with skin tumor promotion.
Main Methods:
- Hairless mice were treated topically with TPA.
- Epidermal histidase activity was measured in postmitochondrial supernatants.
- Enzyme activity was compared between TPA-treated and control groups.
Main Results:
- TPA treatment caused a dose-dependent decrease in epidermal histidase specific activity.
- The decrease in histidase activity occurred within 12 hours and recovered by 5 days post-treatment.
- Other phorbol derivatives and the unrelated promoter Tween 60 also decreased histidase, while initiators did not.
Conclusions:
- TPA-induced decrease in epidermal histidase is associated with tumor promotion, not initiation.
- This finding provides insight into the specific functional aberrations caused by TPA during skin carcinogenesis.