Palmitoylcarnitine reverses 12-O-tetradecanoylphorbol-13-acetate-induced refractory state for the TPA-caused ornithine decarboxylase induction in mouse epidermis

When a single topical application of 12-O-tetradecanoylphorbol-13-acetate(TPA) was performed 12 h before the second application, ornithinedecarboxylase (ODC) induction by the second application of TPAwas markedly suppressed (refractory state). However, at intervalsof 96 h between the first and the second application, the ODCactivity induced by the second application of TPA was higher(enhanced state) than the activity induced by the single application.When various antitumor promoting agents, i.e. p-bromophenacylbromide, nordihydroguaiaretic acid, quercetin, 1-tosylamide-2-phenylethylchloromethyl ketone, retinoic acid and palmitoylcarnitine, wereapplied concurrently with the first TPA application, the ODCinduction in the refractory state was restored only by palmitoylcarnitine,but not by other anti-tumor promoting agents. None of theseanti-tumor promoting agents affected the ODC induction in theenhanced state. Stearoylcarnitine also had the restorative effectbut was less effective than palmitoylcarnitine. Acetylcarnitineand palmitic acid were not effective. Pretreatment of mice withTPA 12 h or 96 h before the second TPA application resultedin the reduction or the increase in the V_max values of ODC bothfor ornithine and pyridoxal-5'-phosphate, respectively. Palmitoylcarnitinerestored these reduced V_max values to the control values. Twelvehours after TPA treatment, the epidermal protein kinase C activityof both cytosol and particulate fractions decreased moderately.At 96 h after TPA application, protein kinase C activities ofboth cytosol and particulate fractions were fully or at leastpartially restored to the control levels. Protein kinase C activitiesboth in the cytosol and the particulate fractions tended tobe restored by palmitoylcarnitine, but the effect was not alwaysreproducible. The TPA-induced refractory state and the enhancedstate for ODC induction appear to result from the changes inthe protein kinase C activities caused by TPA. However, it isnot known whether such changes in the protein kinase C activitiesare the major causes for the TPA-induced refractory and/or enhancedstate for ODC induction and whether or not the restorative effectof palmitoylcarnitine is due to its modulating action on proteinkinase C activity.