Consequences of homocysteine export and oxidation in the vascular system

The risk for arteriosclerosis and thrombosis of patients with severe hyperh omocysteinemia is reduced by homocysteine-lowering therapy. Whether this is the case in patients with mild hyperhomocysteinemia remains to be proved. Another challenge for researchers is to establish a satisfying pathological mechanism of the vasotoxicity of a disturbed homocysteine metabolism Unfor tunately, most in vitro studies use physiologically irrelevant concentratio ns or forms, or both, of homocysteine. The role of the different oxidized a nd reduced forms of homocysteine in its metabolism has gained little attent ion. In the cell, homocysteine is mainly present in its reduced form. In this ar ticle export of homocysteine out of the cell is reported to be regulated by a "reduced-homocysteine carrier." In vitro endothelial cells export homocy steine at a constant rate in a folate dose-dependent matter. Even at high-n ormal folate levels, endothelial cells export homocysteine. As soon as homo cysteine is exported out of the cell, it will be oxidized to a disulfide wi th any compound containing a thiol function or undergo a disulfide exchange reaction, both resulting in formation of disulfides of homocysteine. Conse quently, in plasma, about 99% of homocysteine is bound to disulfides. Befor e homocysteine can be metabolized, it needs to be taken up by the cell via carriers, channels, or receptors recognizing the different homocysteine dis ulfides. In the cell, the homocysteine disulfides are reduced, liberating h omocysteine in its reduced form. Next, homocysteine can be metabolized afte r binding to the homocysteine-converting enzymes. In particular, the liver and kidney supposedly take up and metabolize significant amounts of homocys teine.