Trimetazidine protects low-density lipoproteins from oxidation and cultured cells exposed to H2O2 from DNA damage

Trimetazidine is a well-established anti-ischemic drug, which has been used for long time in the treatment of pathological conditions related with the generation of reactive oxygen species. However, although extensively studi ed, its molecular mode of action remains largely unknown. In the present st udy, the ability of trimetazidine to protect low-density lipoproteins (LDL) from oxidation and cultured cells from H2O2-induced DNA damage was investi gated. Trimetazidine, tested at concentrations 0.02 to 2.20 mM, was shown t o offer significant protection to LDL exposed to three different oxidizing systems, namely copper, Fe/ascorbate, and met-myoglobin/H2O2. The oxidizabi lity of LDL was estimated by measuring, (i) the lag period, (ii) the maxima l rate of conjugated diene formation, (iii) the total amount of conjugated dienes formed, (iv) the electrophoretic migration of LDL protein in agarose gels (REM), and (v) the inactivation of the enzyme PAF-acetylhydrolase pre sent in LDL. In addition, the presence of trimetazidine decreased considera bly the DNA damage in H2O2-exposed Jurkat cells in culture. H2O2 was contin uously generated by the action of glucose oxidase at a rate of 11.8 +/- 1.5 muM per min (60 ng enzyme per 100 mu1), and DNA damage was assessed by the single cell gel electrophoresis assay (also called comet assay). The prote ction offered by trimetazidine in this system (about 30% at best) was trans ient, indicating modification of this agent during its action. These result s indicate that trimetazidine can modulate the action of oxidizing agents i n different systems. Although its mode of action is not clarified, the poss ibility that it acts as a lipid barrier permeable transition metal chelator is considered. (C) 2001 Elsevier Science Inc.