Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity by lipoxygenase inhibitors: possible role of product(s) of lipoxygenase pathway.
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 mumol/mouse), nordihydroguaiaretic acid (30 mumol/mouse) or 3-amino-1-[m-(trifluoromethyl)-phenyl]-2-pyrazoline (BW 755C, 30 mumol/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 mumol/mouse), a selective cyclooxygenase inhibitor, was counteracted by prostaglandin E2 (PGE2) (140 nmol/mouse). This counteracting effect of PGE2 was reversed by the treatment of mice with nordihydroguaiaretic acid (30 mumol/mouse) or phenidone (30 mumol/mouse). ODC activity which was suppressed by nordihydroguaiaretic acid or phenidone at a dose of 180 mumol/mouse was not further inhibited by indomethacin (1.12 mumol/mouse). In addition, the counteracting action of PGE2 (140 nmol/mouse) was not observed in mice treated with nordihydroguaiaretic acid or phenidone at a dose of 180 mumol/mouse. Thus, the suppressive effect of nordihydroguaiaretic acid 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., PGE2) but also lipoxygenase product(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.
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000818:Animals; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D015232:Dinoprostone; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D008084:Lipoxygenase / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors; D051379:Mice; D065108:Ornithine Decarboxylase Inhibitors; D010704:Phorbols / Q000037:antagonists & inhibitors*; D011458:Prostaglandins E / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012867:Skin / Q000201:enzymology*; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors*
D016859:Lipoxygenase Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D010704:Phorbols; D011458:Prostaglandins E; D011720:Pyrazoles; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D008084:Lipoxygenase; D002262:Carboxy-Lyases; C015429:phenidone; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin