Biomedical Engineering Reference
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a
b
500
6.0
5.0
400
R
2
= 0.09
4.0
300
R
2
= 0.39
3.0
200
2.0
100
1.0
0
0.0
5
5.5
6
6.5
7
7.5
5
5.5
6
6.5
7
7.5
pH
pH
Fig. 3.9 Urinary concentrations of Hcy-thiolactone (a), but not tHcy (b), are negatively correlated
with urinary pH (Reproduced from [95])
similar: much higher Hcy-thiolactone concentrations accumulate in urine than in
plasma (the urinary/plasma Hcy-thiolactone ratio is 37 in mice [93] and 100 in
humans [95]). This shows that urinary clearances of Hcy-thiolactone in mice and
humans are similar and that in mice, similar to humans [95],
95 % of the filtered
Hcy-thiolactone is excreted in the urine. Furthermore, significantly higher urinary/
plasma Hcy-thiolactone ratios are found in mice fed hyperhomocysteinemic high-
Met diet than in the animals fed a normal diet, which suggests that efficiency of
urinary Hcy-thiolactone clearance increases in hyperhomocysteinemia.
Renal excretion removes a large fraction of Hcy-thiolactone [95] that would
otherwise cause protein N-homocysteinylation and damage. Thus, urinary excretion
is an important route of Hcy-thiolactone elimination, and intact renal function is
important for Hcy-thiolactone detoxification in humans and mice.
>
3.6 Clinical Significance
show that Hcy-thiolactone is cytotoxic, much more than Hcy itself (e.g., Table
2.2
).
Other studies have found that Hcy-thiolactone is associated with pathological
conditions. For example, plasma Hcy-thiolactone is elevated under conditions
predisposing to atherosclerosis and neurodegenerative diseases, such as caused by
genetic CBS or MTHFR deficiencies in humans [93]. A basal Hcy-thiolactone level
of 0.2 nM in unaffected individuals increases to 14.4 nM and 11.8 nM in CBS
/
and MTHFR
/
patients, respectively (Table
3.6
). Although in these patients tHcy
and N-Hcy-protein are elevated as well, the relative increase in Hcy-thiolactone
significantly exceeds the increases in other Hcy metabolites (Table
3.12
).
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