An Overview of Homocysteine Metabolism - Homocysteine in Protein Structure/Function and Human Disease - page 13

Hcy binding is not affected by 10 mM glutathione and that cysteine does not form a
disulfide with metallothionein [146] suggest that Hcy may bind to metallothionein
by another mechanism, possibly N-homocysteinylation. In fact, Hcy-thiolactone
and protein N-linked Hcy are major Hcy species formed in human endothelial cells
[74]. Similar to other proteins [78], metallothionein contains numerous lysine
residues and is expected to be a target for N-homocysteinylation by Hcy-
thiolactone.

2.2.3 Homocysteine-Thiolactone

Because of its high solubility, relative stability, and odorless character, Hcy-
thiolactone has been often used instead of Hcy to produce experimental
hyperhomocysteinemia in animal models. Early studies, beginning in 1974, well
before biological significance of Hcy-thiolactone was established, have shown that
chronic treatments of animals with Hcy-thiolactone cause pathophysiological
changes akin to those observed in human genetic hyperhomocysteinemia. For
example, continuous Hcy-thiolactone infusions in baboons for 3 months produced
patchy desquamation of vascular endothelium, appearance of circulating endothe-
lial cells, and arterial thrombosis [24]. All Hcy-thiolactone-infused animals devel-
oped typical arteriosclerotic or preatherosclerotic intimal lesions composed of
proliferating smooth muscle cells averaging 10-15 cell layers surrounded by
large amounts of collagen, elastic fibers, glycosaminoglycans, and sometimes
lipid [147]. (Note: That Hcy-thiolactone has been used in Harker et al.'s
experiments [24, 147] is clarified in Mudd et al. [148].) More recent experiments
show that Hcy-thiolactone-supplemented diet for 7 weeks produces atherosclerosis
in rats [149].
In contrast, rabbits are resistant to the detrimental effects of Hcy-thiolactone
infusions [150, 151]. The inability to generate atherosclerosis in rabbits is most
likely due to their high levels of serum Hcy-thiolactonase/PON1, ~tenfold higher
than in humans or other animals. Thus, rabbits turn over serum Hcy-thiolactone
much more efficiently than other animals [81, 152, 153]. Hcy-thiolactone infused
into rabbits is quickly cleared from the blood (within 15 min) [150].

Chronic treatments with Hcy-thiolactone cause developmental abnormalities in
chick embryos [154]. Remarkably, these abnormalities include optic lens disloca-
tion [155] that is identical to the ocular phenotype (ectopia lentis) prevalent in
human CBS deficiency [20, 29, 30]. This finding suggests that ectopia lentis is
caused by elevations of Hcy-thiolactone that are in fact observed in CBS-deficient
patients [93].
Acute treatments with Hcy-thiolactone are also known to cause toxicity in
experimental animals. For example, intraperitoneal infusions of Hcy-thiolactone
into mice or rats, which are used as a model to study mechanisms of epilepsy, cause
seizures and death within minutes [156-159]. Exposure of mouse [160] or rat [142]
embryos

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to Hcy-thiolactone causes lethality, growth retardation, and