NATURAL (ALPHA-TOCOPHEROL) AND SYNTHETIC (PHENOSAN POTASSIUM-SALT) ANTIOXIDANTS REGULATE THE PROTEIN-KINASE-C ACTIVITY IN A BROAD CONCENTRATION RANGE (10(-4)-10(-20)M)

The effects of natural lipid-soluble antioxidant, alpha-tocopherol (al pha-TL), and the synthetic water-soluble antioxidant, phenosan potassi um salt (Ph-K), in a broad range of concentrations down to ultralow do ses (10(-4)-10(-20) M) on the activity of protein kinase C (PKC) have been studied. It was shown that alpha-TL is a potent inhibitor of the rabbit heart enzyme: the maximum extent of inhibition is 80%. The effe cts of alpha-TL on the main kinetic parameters of the PKC activity dif fer at the alpha-TL physiological (10(-4) M) and ultralow (10(-14) M) concentrations: at 10(-14) M, alpha-TL acts as an allosteric inhibitor with Hill's coefficient about 2 and increases the PKC affinity to the substrate (histone H-1) by 2 times. It was concluded that alpha-TL is more efficient inhibitor at ultralow concentration. Ph-K added to nor mal (A7r5 rat vascular smooth muscle cells, VSMC) and tumor cells (Sao s-2 human osteosarcoma) growing in a culture has been found to be a PK C superactivator. The maximum activation is 400-500%, which exceeds th e effect of the best activator of this enzyme, phorbol ester (TPA), by more than two times. It was demonstrated that irrespective of the eff ector action (activation or inhibition), the dose-effect curves are of the bimodal type with two maxima at the high (or physiological) (10(- 4)-10(-7) M) and ultralow (10(-14)-10(-19) M) concentrations of the an tioxidants and so-called ''silence zone'' between them, in which the e ffect of antioxidants is significantly reduced or absent (tumor cells) . For the first time, these bimodal curves were observed at the enzyme level. The results obtained were discussed considering various hypoth esises on the effect of ultralow doses of biologically active compound s and the PKC activity regulation in normal and tumor cells by the ant ioxidants.