Introduction - Homocysteine in Protein Structure/Function and Human Disease - page 3

4.4 % methionine) experience accelerated atherosclerosis (at 3 months), start to lose
weight, and die prematurely (48 % animals die at 8 months) [18]. Chicks fed with
a high-methionine (2 %) diet develop hyperhomocysteinemia, neurological seizures,
and severe aortic pathology resulting from aberrant assembly of elastic fibers [19].
Elevation of Hcy in body tissues, further exacerbated when intake of B vitamins and
folate (cofactors of Hcy-metabolizing enzymes; Fig. 1.1 ) is inadequate, contributes to
the toxicity of methionine excess [20]. Conversely, methionine restriction increases
life span in rats [21] and inhibits age-related disease processes [22], including cancer
[23]. The administration of Hcy itself is often used to study mechanisms underlying
the pathology of hyperhomocysteinemia in experimental animals [18, 24, 25].
In humans, the administration of methionine at a dose of 0.1 g/kg body weight is
used to test for deficiencies in Hcy metabolism and to study relationships between
elevation of plasma Hcy and cardiovascular and neurodegenerative diseases. The
oral methionine loading test is generally very safe [26, 27]. However, a larger dose
of methionine may cause severe, potentially lethal cerebral effects: one case of
death of a control subject participating in a study of relationships between Hcy and
Alzheimer's disease has been reported to result from a substantial overdose of
methionine (80 g instead of the usual 8 g) [28].
Inborn errors in human Hcy metabolism due to mutations in the cystathionine

β -synthase (CBS), 5,10-methylenetetrahydrofolate reductase (MTHFR), or methi-

onine synthase (MS) genes (Fig. 1.1 ) cause severe hyperhomocysteinemia and
homocystinuria as well as pathologies in multiple organs, including the cardiovas-
cular system and the brain, and lead to premature death due to vascular
complications, usually thromboembolism in affected arteries and veins [20,
29-32]. Observations of advanced arterial lesions in children with inborn errors
in Hcy metabolism have led to a proposal that Hcy causes vascular disease [33].
Severe hyperhomocysteinemia is rare. For example, CBS deficiency occurs at an
estimated worldwide frequency of 1 in 300,000, with higher frequency in Ireland
(1 in 65,000) and Qatar (1 in 1,800). In contrast, mild hyperhomocysteinemia is
quite prevalent in the general population (some estimates indicate a frequency as
high as 1 in 10) and is also associated with an increased risk [34] of cardiovascular
disease and mortality [35-37], neurological complications [38], pregnancy
complications and birth defects [39], and osteoporosis [40]. Although associations
alone do not prove causality, preponderance of experimental evidence indicates that
it is biologically plausible that excess Hcy can damage and impair normal cellular
and physiological function and cause disease [9, 41].
Atherosclerosis is a disease of the vascular wall and is initiated by endothelial
damage [42, 43]. Endothelial dysfunction, immune activation, and thrombosis,
characteristic features of vascular disease [42, 43], are all observed in hyperhomo-
cysteinemic individuals [20] and experimental hyperhomocysteinemia in animals
[14, 44, 45]. The degree of endothelial function impairment in hyperhomocys-
teinemic organisms is similar to that observed in subjects with hypercholesterol-
emia or hypertension [44].
The strongest evidence that elevated Hcy plays a causal role in atherothrombotic
disease comes from studies of severe genetic hyperhomocysteinemia in humans and