METABOLIC CONVERSION OF 12-O-TETRADECANOYLPHORBOL-13-ACETATE IN ADULT AND NEWBORN MOUSE SKIN AND MOUSE-LIVER MICROSOMES

Google Scholar
  • 1 January 1978
    • journal article
    • research article
    • Vol. 38  (8) , 2301-2306
Abstract
3H-12-O-Tetradecanoylphorbol-13-acetate (TPA) was applied to adult mouse skin. At specified time intervals the mice were killed, and the labeled phorbol was extracted and subjected to separation and quantitation by high-pressure liquid chromatography. After 24 h, TPA comprised > 96% of the recovered label from the skin, and its apparent half-life was 17.8 h. Pretreatment of adult skin with TPA for 4 wk before treatment with labeled TPA resulted in an increase in the clearance rate of TPA from the skin. Skin from newborn mice was capable of converting TPA into monoesters and phorbol, but the clearance rate in the adult was about 12 times more rapid than it was in the newborn. Epidermal homogenates converted TPA into 12-O-tetradecanoylphorbol, phorbol-13-acetate and phorbol. Hepatic homogenates were able to convert TPA to monoesters and phorbol at rates 14 to 15 times faster than epidermal homogenates. Attempts to isolate any previously undescribed metabolites of TPA by use of liver homogenates were unsuccessful, and mixed-function oxidation did not contribute to the metabolism of TPA. From inhibitor studies it was judged that esterases were implicated in the conversion of TPA to monoesters and phorbol. The results support the hypothesis that the tumor-promoting activity of TPA is directly related to its concentration in a specific tissue and conversion of TPA to an active metabolite probably does not occur.