Inhibitory effect of oleanolic acid on 12-O-tetradecanoylphorbol-13-acetate-induced gene expression in mouse skin.

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 mumol) 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 metallothionein (MT) gene expression in mouse skin. A dose of 2.5 mumol of OA diminished the TPA-induced MT mRNA 50%. Treatment with OA (10 mumol) 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.