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© 1998 Oxford University Press

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Inhibitory Effect of Oleanolic Acid on 12-O-Tetradecanoylphorbol-13-acetate-lnduced Gene Expression in Mouse Skin

Takiko Oguro*, Jie Liu{dagger}, Curtis D. Klaassen{dagger} and Takemi Yoshida*

*Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142, Japan {dagger}Department of Pharmacology, Toxicology and Therapeutics, Environmental Health and Occupational Medicine Center, University of Kansas Medical Center Kansas City, Kansas 66160-7417

Received December 31, 1997; accepted May 1, 1998

Oleanolic acid (OA) has been shown to inhibit mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). This study was designed to examine the effect of OA on the TPA-induced expression of the ornithine decarboxylase (ODC) gene as well as other genes. OA inhibited the induction of ODC activity and mRNA level produced by TPA in the skin of female CD-1 mice. Preapplication of OA (10 µmol) to the mouse dorsal skin produced an approximately 50% decrease in TPA (8 nmol)induced epidermal ODC activity, as well as ODC gene expression. These results suggest that OA inhibits TPA-induced ODC mainly at the transcriptional level. In addition to ODC, TPA also stimulated metallothionetn (MT) gene expression in mouse skin. A dose of 2.5 µmol of OA diminished the TPA-induced MT mRNA 50%. Treatment with OA (10 µmol) after TPA (8 nmol) application also inhibited ODC and MT gene expression which suggests that OA does not compete with TPA for its receptor. OA pretreatment also prevented c-fos gene expression. All of these findings suggest that OA diminishes some signal transduction pathways of TPA to suppress target gene expression in mouse skin. This study suggests that OA might be a general inhibitor against TPA-stimulated gene expression in mouse skin.

Key Words: oleanolic acid; 12-0-tetradecanoylphorbol-13-ace-tate; ornithine decarboxylase; metallothionein; c-fos; gene expression; mouse; skin..


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