Ascorbic acid augments cytotoxicity induced by oxidized low-density lipoprotein.

Although ascorbic acid (ASA) is known as a water-soluble antioxidant, we found that it accelerated the cytotoxicity induced by oxidized low-density lipoprotein (OxLDL) in vitro. This suggests that ASA may enhance the oxidation of LDL to augment the atherogenic activities of OxLDL under certain conditions. Thus, this study was designed to investigate the underlying mechanism that ASA enhances OxLDL-induced cytotoxicity. ASA enhanced the cytotoxicity of macrophage cell line (J774) induced by OxLDL in a dose-dependent manner, whose effect was more apparent in high glucose concentration in the medium. The ASA-induced enhancement in cytotoxicity was inhibited by the presence of lipid-soluble antioxidants, such as alpha-tocopherol and probucol, suggesting that the pro-cytotoxic effect by ASA is likely due to its pro-oxidant property. We also investigated the effects of ASA at different time points on the Cu2+-mediated oxidation of LDL. ASA decreased the rate of conjugated dienes formation when added at the early phase of oxidation, whereas it increased when added at the late phase of oxidation. These data suggest that ASA may act as a pro-oxidant under the condition of extensive LDL oxidation. To prevent oxidation stress, ASA would be better used together with lipid-soluble antioxidants for antioxidant therapies.