Introduction - Homocysteine in Protein Structure/Function and Human Disease - page 4

the finding that Hcy lowering by B-vitamin supplementation significantly improves
vascular outcomes in CBS-deficient patients [20, 29, 30]. For instance, while
untreated CBS-deficient patients suffer one vascular event per 25 patient-years
[46], B-vitamin-treated CBS-deficient patients suffer only one vascular event per
263 patient-years (relative risk 0.091, p < 0.001) [30]. Hcy-lowering therapy

initiated early in life also prevents brain disease from severe MTHFR deficiency
[31, 47]. Furthermore, studies of genetic or nutritional hyperhomocysteinemia in
animal models also provide a strong support for a causative role of Hcy [14, 44, 48].
In humans, lowering plasma Hcy by B-vitamin supplementation improves cog-
nitive function in the general population [49] and leads to a 21-24 % reduction of
vascular outcomes in high-risk stroke patients [50, 51], but not in myocardial
infarction patients [51, 52]. Meta-analysis of Hcy-lowering trials provides evidence
that folic acid supplementation can significantly reduce the risk of stroke in primary
prevention, provided that the intervention lasts

3 years and results in tHcy

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lowering 20 % [53]. Among possible reasons cited for the failure of B-vitamin

intervention trials to prevent adverse vascular outcomes is that the beneficial effect
of B-vitamin therapy in lowering plasma Hcy is counteracted by adverse effects of
high B-vitamin levels on the cardiovascular system [10].
As demonstrated by a post hoc subanalysis of the VITATOPS trial [54], benefits
of B-vitamin therapy to lower Hcy are offset by concomitant use of antiplatelet
therapy. Combined analyses of two randomized Hcy-lowering B-vitamin trials, the
Norwegian Vitamin Trial (NORVIT) and the Western Norway B Vitamin Inter-
vention Trial (WENBIT), suggest that cardiovascular risk prediction is confined to
the fraction of Hcy that does not respond to B vitamins [55]. Hcy lowering by
B-vitamin treatment slows the rate of accelerated brain atrophy [56] and cognitive
decline [57] in mild cognitive impairment patients, which may slow or prevent the
conversion to dementia and Alzheimer's disease.
Although it is a common metabolite in all living organisms, Hcy in excess of
basal levels can be extremely toxic to human [58-61], animal [62], yeast [63-65],
and bacterial cells [66, 67]. Why Hcy is toxic is not entirely clear and is a subject of
intense investigations, particularly in the context of human pathophysiology [41,
44, 68-71].
Hcy is one of the most reactive amino acids and participates in at least seven
reactions in biological systems [68]. In addition to its elimination by remethylation
to methionine, transsulfuration to cysteine (via cystathionine), and oxidation to
disulfides, Hcy is also metabolically converted to other, potentially toxic,
metabolites (Fig. 1.1 ), such as Hcy-thiolactone, N-Hcy-protein, Nε

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-Hcy-Lys [72],
AdoHcy, homocysteic acid, or S-nitroso-Hcy; these conversions can be greatly
enhanced in genetic or nutritional deficiencies in Hcy metabolism. Possible
mechanisms accounting for the toxicity of specific Hcy metabolites have been
proposed. However, because of parallel changes in the concentrations of Hcy
metabolites under most clinical and experimental circumstances, it is often difficult
to unequivocally assign the observed toxicity to a specific Hcy metabolite.
As discovered at the end of 1990s, two of these metabolites, Hcy-thiolactone
[73, 74] and S-nitroso-Hcy [75, 76], mediate Hcy incorporation into protein [77].