Trimetazidine protects low-density lipoproteins from oxidation and cultured cells exposed to H(2)O(2) 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 studied, its molecular mode of action remains largely unknown. In the present study, the ability of trimetazidine to protect low-density lipoproteins (LDL) from oxidation and cultured cells from H(2)O(2)-induced DNA damage was investigated. Trimetazidine, tested at concentrations 0.02 to 2.20 mM, was shown to offer significant protection to LDL exposed to three different oxidizing systems, namely copper, Fe/ascorbate, and met-myoglobin/H(2)O(2). The oxidizability of LDL was estimated by measuring, (i) the lag period, (ii) the maximal 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 present in LDL. In addition, the presence of trimetazidine decreased considerably the DNA damage in H(2)O(2)-exposed Jurkat cells in culture. H(2)O(2) was continuously generated by the action of glucose oxidase at a rate of 11.8 +/- 1.5 microM per min (60 ng enzyme per 100 microl), and DNA damage was assessed by the single cell gel electrophoresis assay (also called comet assay). The protection offered by trimetazidine in this system (about 30% at best) was transient, indicating modification of this agent during its action. These results indicate that trimetazidine can modulate the action of oxidizing agents in different systems. Although its mode of action is not clarified, the possibility that it acts as a lipid barrier permeable transition metal chelator is considered.
Tselepis
A
A
Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece.
Doulias
P
P
Lourida
E
E
Glantzounis
G
G
Tsimoyiannis
E
E
Galaris
D
D
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000975:Antioxidants / Q000494:pharmacology*; D002614:Chelating Agents / Q000494:pharmacology; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology* / Q000633:toxicity; D007091:Image Processing, Computer-Assisted; D019169:Jurkat Cells / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D010741:Phospholipases A / Q000032:analysis; D014292:Trimetazidine / Q000494:pharmacology*
D000975:Antioxidants; D002614:Chelating Agents; D008077:Lipoproteins, LDL; D006861:Hydrogen Peroxide; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D014292:Trimetazidine