Modulation of extracellular homocysteine concentration in human cell lines

Background: Despite the growing evidence that plasma homocysteine is a cardiovascular risk factor, the mechanism behind the vascular injuries is still unknown. Information about the metabolism of homocysteine is, therefore, essential for an understanding of its role in atherogenesis, thereby enabling a modulation of that risk. Methods: In the present study, we have examined the modulation of extracellular homocysteine in HeLa and hepatoma cell cultures in relation to a changed extracellular thiol redox status and in the presence of specific inhibitors of amino acid transporters. Results: The findings in the present study show that a changed thiol redox status by copper ions, copper chelator or the monothiol, N-acetylcysteine (NAC), affects extracellular homocysteine in the same way in hepatoma cell cultures, but not to the same extent as observed in HeLa cell cultures. However, the dithiols, dithiothreitol (DTT) and alpha-lipoic acid (LA), which lowered extracellular homocysteine concentration in HeLa cell cultures, increased the extracellular total homocysteine concentration in hepatoma cell cultures, probably mainly as a result of increased release of homocysteine extracellularly. Studies with specific inhibitors of amino acid transporters in HeLa cell cultures showed that homocysteine uptake occurred mainly by system A and glutamate transporters. Hepatoma cells seemed to have a much smaller uptake capacity of homocysteine compared to HeLa cells. Conclusion: The lack of uptake capacity of homocysteine in hepatoma cells indicates that hepatocytes only play a small role in the elimination of homocysteine from circulation. Intracellular metabolism, cellular export and the complex pattern of homocysteine uptake in different cells are important to examine further in order to possibly be able to lower plasma homocysteine levels. (C) 2003 Elsevier Science B.V. All rights reserved.