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Differences in the Metabolism of 12-O-[³H]Tetradecanoylphorbol-13-acetate and [³H]Phorbol-12,13-didecanoate by Cells in Culture¹

The Wistar Institute, Philadelphia, Pennsylvania 19104

The metabolism of the tumor promoters 12-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.

¹ Supported in part by USPHS Research Grants ES-01664, awarded by the National Institute of Environmental Health Sciences, and CA-23413 and CA-21778, awarded by the National Cancer Institute, Department of Health, Education and Welfare.

² To whom requests for reprints should be addressed.

Received 5/12/80. Accepted 8/20/80.