THE EFFECT OF PHORBOL ESTERS ON THE LIPID -PEROXIDATION IN THE MEMBRANES OF ENDOPLASMIC-RETICULUM ISOLATED FROM MOUSE-LIVER

It is known that 12-O-tetradecanoylphorbol-13-acetate (TPA) is a tumor , promotor and secondary messenger modifier, whereas 4-alpha-phorbol-1 2,13-didecanoate (DDP) displays no similar properties. Recently, we fo und that TPA induces significant changes in the microviscosity of diff erent lipid domains of biological membranes. Because the structural fa ctor is very important in the initiation and propagation of the lipid peroxidation (LPO), we studied the TPA and DDP effects in a wide range of concentration (10(-16)-10(-3) M) on LPO in the membranes of the en doplasmic reticulum isolated from mouse liver. It was shown that TPA i nhibits LPO, while DDP does not affect the process. It is especially i mportant that ultra-low TPA concentrations (10(-14)-10(-11) M) produce d the maximal effect. LPO inhibition was registered both on the basis of increase in the content of primary (hydroperoxides) and secondary ( malone dialdehyde - MDA) oxidation products and on the expenditure of the unsaturated substrate (total double bound - DB - content). LPO inh ibition determined on the basis of secondary products (MDA) was higher than the inhibition determined on the basis of the primary products. Kinetic constants of DB decrease were 4,46 . 10(-2) min(-1) in control microsomes and 1,7 . 10(-2) min(-1) after treatment with 10(-12) M TP A respectively. Experiments on the mechanism of TPA action indicated t hat it did not react with lipid hydroperoxides, but, probably affected the free radical stages of LPO. The most characteristic feature of TP A in comparison to the <<classical>> antioxidants is its effective act ion in the significantly lower concentrations (by 10 orders). It is po ssible to conclude that any additional way of TPA action on LPO is rel ated to its effect on the membrane structure.