Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity by lipoxygenase inhibitors: possible role of product(s) of lipoxygenase pathway

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Abstract
Induction of epidermal ornithine decarboxylase (ODC) by a topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA), a tumor promoter, was inhibited by treatment of mouse skin with phenidone (3–90 μ mol/mouse), nordihydroguaiaretic add (30 μmol/mouse) or 3-amino-1-[ m -(trifluoromethyl)-phenyl]-2-pyrazoline (BW 755C, 30 μ/mouse), which are well-known lipoxygenase inhibitors. Phenidone and BW 755C are also to be cyclooxygenase inhibitors. Inhibition of TPA-induced ODC by indomethacin (1.12 μmol/mouse), a selective cyclooxygenase inhibitor, was counteracted by prostaglandin E 2 (PGE 2 ) (140 nmol/mouse). This counteracting effect of PGE 2 was reversed by the treatment of mice with nordihydroguaiaretic acid (30 μmol/mouse) or phenidone (30 umol/mouse). ODC activity which was suppressed by nordihydroguaiaretic add or phenidone at a dose of 180 umol/mouse was not further inhibited by indomethadn (1.12 μmol/mouse). In addition, the counteracting action of PGE 2 (140 nmol/mouse) was not observed in mice treated with nordihydroguaiaretic acid or phenidone at a dose of 180 umol/mouse. Thus, the suppressive effect of nordihydroguaiaretic add or phenidone on the ODC induction by TPA would be due to the inhibition of lipoxygenase. The above findings strongly suggest that not only cyclooxygenase product (i.e., PGE 2 ) but also lipoxygenase produces(s) are involved in the mechanism of ODC induction in mouse epidermis, and a lack of either cyclooxygenase product or lipoxygenase product(s) causes a failure of ODC induction by TPA.