An Overview of Homocysteine Metabolism - Homocysteine in Protein Structure/Function and Human Disease - page 11

children after methotrexate treatment [119]. HSA and HCA are both identified in
urine from CBS-deficient patients but not in urine from normal individuals [120].
Extremely high HCA concentrations are reported to be present in plasma (up to

23 M) and in urine (up to 25 mM) of Alzheimer's disease patients, whereas in

control individuals, the HCA levels are somewhat lower (by 40 %) [121]. Such
HCA concentrations are 100-10,000-fold higher than HCA values reported by
other investigators. Unfortunately, Hasegawa et al. [121] do not discuss these
discrepancies and give only a very limited experimental detail for their assay,
which prevents any rational explanation of their data.
In rats, oral administration of Hcy increases plasma HCA from an undetectable
level to 2.0

μ

M [122]. Methotrexate treatment elevates both HSA and HCA in rat
cerebrospinal fluid [123]. HCA is also reported to be present in mouse brain and
urine, at 2.3

μ

M, respectively [124].
HCA has been reported to arise by spontaneous oxidation of Hcy [125]. It can
also form by the radiolytic degradation of methionine and methionine-containing
peptides [126] and from photooxidation of methionine peptides induced by hydro-
gen peroxide and UV laser light [127]. Analysis of archived samples from a
previously unreported 1958 Stanley Miller's origin of life experiment shows that
HCA and other sulfur amino acids are generated in spark discharge experiments
designed to imitate primordial environments [128]. Prebiotic formation of methio-
nine in spark discharges in a simulated primitive earth atmosphere containing CH 4 ,
N 2 ,NH 3 ,H 2 O, and H 2 SorCH 3 SH has been reported in 1972 [129].

μ M and 22.5 μ

2.2 Toxicity of Homocysteine Metabolites

Acute exposure of living cells and organisms to excess Hcy is known to cause
cellular toxicity [7, 68]. The presence of multiple molecular Hcy species raises a
question regarding whether any of those species could be more harmful than the
other. Numerous clinical and animal studies have established that chronic elevation
of plasma tHcy is associated with cardiovascular and neurological abnormalities
[34, 36, 37], most severely manifested in genetic deficiencies in Hcy (CBS) [20],
folate (MTHFR, PCFT) [31, 130], and cobalamin (cblC) [131, 132] metabolism.
However, it should be noted that tHcy is a composite marker, comprised of at least
five different Hcy species [87, 102], each of which could exert a distinct biological
effect. Moreover, tHcy does not encompass other Hcy metabolites present in the
human blood, such as Hcy-thiolactone [94, 95], N-Hcy-protein [79, 115], Nε -Hcy-

Lys [72], AdoHcy, cystathionine, and homocysteic acid [68]. Thus, a contribution
of an individual Hcy species to cardiovascular risk or mortality is likely to be
obscured by using tHcy as a marker [133]. Indeed, in a few studies that addressed
this issue, plasma AdoHcy [116] and anti-N-Hcy-protein autoantibodies [134, 135]
turned out to be much more sensitive indicators of human cardiovascular disease
than plasma tHcy.