Differences in the metabolism of 12-O-[3H]tetradecanoylphorbol-13-acetate and [3H]phorbol-12,13-didecanoate by cells in culture.

The metabolism of the tumor promoters 120-O-[3H]tetradecanoylphorbol-13-acetate ([3H]TPA) and [3H]phorbol-12,13-didecanoate ([3H]PDD) was analyzed in several cell types in culture. In contrast to the rapid metabolism of [3H]TPA, [3H]PDD was degraded much more slowly in hamster, rat, chick, and mouse fibroblasts. Human fibroblasts did not significantly metabolize either phorbol diester over a three-day period. In hamster fibroblasts, addition of increasing amounts of nonradioactive TPA inhibited the metabolism of [3H]TPA, while a 100-fold excess of PDD had no effect on [3H]TPA metabolism. Primary cultures of hamster epidermal cells, a long-term epidermal cell line, and a hamster preadipose cell line rapidly metabolized [3H]TPA but only slowly metabolized [3H]PDD. In contrast to human fibroblasts, a human hepatoma cell line metabolized [3H]TPA, but these cells metabolized [3H]PDD much more slowly. The profile of metabolites produced from [3H]PDD was studied in two cell types. In hamster cells, the major metabolite produced was [3H]phorbol-12-decanoate while in BALB/c 3T3 cells, approximately equal amounts of [3H]phorbol-12-decanoate and [3H]phorbol-13-decanoate were produced. When tested for biological activity in cell culture, phorbol-13-decanoate was 17 to 40 times less active than PDD as measured by the induction of ornithine decarboxylase in hamster cells and the stimulation of 2-deoxyglucose uptake in BALB/c 3T3 cells. Phorbol-12-decanoate was virtually inactive in both assays.