L'homocysteine est un acide amine soufre qui est soit methyle en methionine soit transforme en cystathionine et cysteine par la voie de la transsulfuration dependant de la vitamine B 6 . La premiere voie a pour cofacteur la vitamine B 1 2 et utilise comme donneur de methyle soit un derive de l'acide folique, le N5-methyltetrahydrofolate, soit la betaine. La remethylation et la transsulfuration de l'homocysteine sont regulees de facon coordonnee par la S-adenosylmethionine (SAM) qui inhibe l'activite methylenetetrahydrofolate reductase (MTHFR), l'enzyme catalysant la synthese du N5-CH 3 THF a partir du methylenetetrahydrofolate et stimule l'activite cystathionine beta-synthase. Toute perturbation metabolique de l'une de ces deux voies entraine une hyperhomocysteinemie. Une hyperhomocysteinemie severe est generalement engendree par un deficit congenital en cystathionine beta-synthase (CBS). Une hyperhomocysteinemie moderee est observee a jeun soit du fait de la mutation du gene codant pour la MTHFR soit a cause d'une alteration du statut vitaminique B 9 ou B 1 2 . L'hyperhomocysteinemie moderee observee apres une surcharge en methionine traduit plutot un defaut de la voie de transsulfuration (mutation du gene codant pour la CBS, deficience en vitamine B 6 ). Les sujets atteints d'homocystinurie ont des valeurs d'homocysteinemie tres elevees et presentent des l'enfance des accidents vasculaires, thromboemboliques ou plus rarement lies a l'atherosclerose. Des concentrations elevees d'homocysteine provoquent des lesions anatomiques de l'endothelium vasculaire, stimulent la proliferation des cellules musculaires lisses arterielles et la production des mediateurs de l'inflammation. Ces effets sont supposes medies par l'oxydation de l'homocysteine et la production d'especes radicalaires derivees de l'oxygene et aussi par interference avec la production du NO et de nombreux facteurs de transcription, la transduction de signaux cellulaires, l'oxydation des LDL et la diminution de la vasodilatation dependant de l'endothelium.
Recent epidemiological studies have suggested that hyperhomocysteinemia is associated with increased risk of vascular disease. Homocysteine is a sulphur-containing amino acid whose metabolism stands at the intersection of two pathways: remethylation to methionine, which requires folate and vitamin B 1 2 (or betaine in an alternative reaction); and transsulfuration to cystathionine which requires vitamin B 6 . The two pathways are coordinated by S-adenosylmethionine which acts as an allosteric inhibitor of the methylenetetrahydrofolate reductase (MTHFR) and as an activator of cystathionine β-synthase (CBS). Hyperhomocysteinemia arises from disrupted homocysteine metabolism. Severe hyperhomocysteinemia is due to rare genetic defects resulting in deficiencies in CBS, MTHFR, or in enzymes involved in methyl cobalamine synthesis and homocysteine methylation. Mild hyperhomocysteinemia seen in fasting condition is due to mild impairment in the methylation pathway (i.e. folate or B 1 2 deficiencies or MTHFR thermolability). Post-methionine-load hyperhomocysteinaemia may be due to heterozygous cystathionine-β-synthase defect or B 6 deficiency. Patients with homocystinuria and severe hyperhomocysteinemia develop arterial thrombotic events, venous thromboembolism, and more seldom premature arteriosclerosis. Experimental evidence suggests that an increased concentration of homocysteine may result in vascular changes through several mechanisms. High levels of homocysteine induce sustained injury of arterial endothelial cells, proliferation of arterial smooth muscle cells and enhance expression/activity of key participants in vascular inflammation, atherogenesis, and vulnerability of the established atherosclerotic plaque. These effects are supposed to be mediated through its oxidation and the concomitant production of reactive oxygen species. Other effects of homocysteine include: impaired generation and decreased bioavailability of endothelium-derived relaxing factor/nitric oxide; interference with many transcription factors and signal transduction; oxidation of low-density lipoproteins; lowering of endothelium-dependent vasodilatation. In fact, the effect of elevated homocysteine appears multifactorial affecting both the vascular wall structure and the blood coagulation system.