Homocysteine-Thiolactone - Homocysteine in Protein Structure/Function and Human Disease - page 51

Table 3.12 Human genetic hyperhomocysteinemia: Mutations in MTHFR or CBS gene increase
plasma Hcy-thiolactone and N-Hcy-protein (Recalculated from [93, 115])

Fold increase relative to unaffected individuals
N-Hcy-protein Genotype (n) Hcy-thiolactone tHcy

MTHFR / , before therapy (1) 31.4 237 31.0

MTHFR /a (4)

9.0 59 7.5

MTHFR +/ (6) 2.2 2.5 1.2

Unaffected (9) 1 (0.49 0.08 μM) 1 (0.2 0.14 nM) 1 (6.7 1.9 μM)

CBS /a (29) 6.2 72 7.2

CBS / , noncompliant (1) 24.7 43.9

a

MTHFR / and CBS / patients were on an Hcy-lowering therapy

In a study of 120 Chinese patients with type 2 diabetes and 40 healthy controls,
tHcy and Hcy-thiolactone levels are associated with the development and progres-
sion of diabetic macrovasculopathy (MAVP) [362]. Plasma tHcy and Hcy-
thiolactone are found to be significantly elevated in the patients (tHcy [25th and
75th quartiles]: 9.28 [7.51-11.82] vs. 5.64 [5.17-8.00] μ M, P ¼ 0.01; Hcy-

thiolactone: 3.38 [2.94-4.73] vs. 2.91 [2.77-3.08] nM, P < 0.05). Plasma tHcy

and Hcy-thiolactone levels in patients with MAVP are significantly higher com-
pared with patients without MAVP (Hcy: 10.36 [7.67-12.45] vs. 7.85
[6.76-10.52] μM, P < 0.05; Hcy-thiolactone: 4.27 [3.02-5.11] vs. 3.12

[2.63-3.77] nM, P < 0.05).

Furthermore, plasma Hcy-thiolactone concentrations are positively correlated
with urinary excretion of albumin/creatinine (Alb/Cr; r ¼

0.285, P ¼ 0.007),

duration of diabetes (r ¼ 0.249, P ¼ 0.019), age (r ¼ 0.233, P ¼ 0.028), and

fibrinogen levels (r ¼ 0.289, P ¼ 0.034). However, plasma Hcy-thiolactone

concentrations are negatively correlated with HDL levels (r ¼ 0.223,

P ¼ 0.037) [362], consistent with the ability of HDL-associated PON1 protein to

hydrolyze Hcy-thiolactone [81]. Binary logistic regression shows that Hcy-
thiolactone, tHcy, smoking, serum triglyceride, and urinary Alb/Cr are significantly
associated with the risk of diabetic MAVP (P < 0.05) [362]. Taken together, these

findings suggest that Hcy-thiolactone provides a plausible chemical mechanism for
explaining the toxicity of hyperhomocysteinemia to the human vascular endothe-
lium discussed in a greater detail in Chapter 6).
An ongoing study under the direction of the author of this topic is examining
determinants of Hcy-thiolactone excretion in human urine in patients with coronary
artery disease, with a major goal to evaluate the prognostic effect of urinary Hcy-
thiolactone on the risk of subsequent myocardial infarction and mortality. The study
is using urine samples from the Western Norway B Vitamin Intervention Trial
(WENBIT) [55]. Another goal is to analyze how urinary Hcy-thiolactone levels are
affected by B-vitamin supplementation. Also being analyzed are associations of
Hcy-thiolactone levels with subsequent myocardial infarction (cardiovascular
death, nonfatal myocardial infarction) and mortality. The usefulness of Hcy-
thiolactone as a predictor of these outcomes will be determined. Associations of
Hcy-thiolactone with CVD history, gender, smoking, hypertension, diabetes,