Consequences of homocysteine export and oxidation in the vascular system.
The risk for arteriosclerosis and thrombosis of patients with severe hyperhomocysteinemia 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. Unfortunately, most in vitro studies use physiologically irrelevant concentrations or forms, or both, of homocysteine. The role of the different oxidized and reduced forms of homocysteine in its metabolism has gained little attention. In the cell, homocysteine is mainly present in its reduced form. In this article export of homocysteine out of the cell is reported to be regulated by a "reduced-homocysteine carrier." In vitro endothelial cells export homocysteine at a constant rate in a folate dose-dependent matter. Even at high-normal folate levels, endothelial cells export homocysteine. As soon as homocysteine is exported out of the cell, it will be oxidized to a disulfide with any compound containing a thiol function or undergo a disulfide exchange reaction, both resulting in formation of disulfides of homocysteine. Consequently, in plasma, about 99% of homocysteine is bound to disulfides. Before homocysteine can be metabolized, it needs to be taken up by the cell via carriers, channels, or receptors recognizing the different homocysteine disulfides. In the cell, the homocysteine disulfides are reduced, liberating homocysteine in its reduced form. Next, homocysteine can be metabolized after binding to the homocysteine-converting enzymes. In particular, the liver and kidney supposedly take up and metabolize significant amounts of homocysteine.
Blom
H J
HJ
Department of Pediatrics, University Hospital Nijmegen, The Netherlands. h.blom@ckslkn.azn.nl
D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism; D001773:Blood Cells / Q000378:metabolism; D002319:Cardiovascular System / Q000378:metabolism*; D004220:Disulfides / Q000097:blood; D004730:Endothelium, Vascular / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D019851:Thrombophilia / Q000209:etiology / Q000378:metabolism
D004220:Disulfides; D006710:Homocysteine