Homocysteine-Thiolactone - Homocysteine in Protein Structure/Function and Human Disease - page 46

Table 3.10 Blmh / and Pon1 / mice are more susceptible to Hcy-thiolactone neurotoxicity
than wild-type littermates. The mice are injected intraperitoneally with L -Hcy-thiolactone
(3,700 nmol g 1 body weight) and monitored for neurological manifestations for 90 min (Adapted
from [140, 141])

Incidence of
seizures, % (n)

Incidence of death,
%(n)

Seizure latency
period, min

Death latency
period, min Genotype (n)

Blmh / (32) 93.8 (30)* 46.9 (15)* 33.1 10.1*** 46.6 15.1

Pon1 / (36)

52.8 (19)** 8.3 (3) 31.8 11.6**** 50 30

Wild type (44) 29.5 (13) 2.3 (1) 41.2 10.8 61

*, **, ***, ****Significantly different from wild type—Fisher exact test *P < 0.001,

**P ¼ 0.042 vs. wild type; T test ***P ¼ 0.012, ****P ¼ 0.019 vs. wild type

the incidence of death is somewhat increased for Pon1 / mice (to 3 out of 36
Pon1 / mice, 8.3 %). Pon1 / mice have elevated postinjection levels of N-Hcy-
protein in the brain, compared with wild-type Pon1 +/+ littermates, which suggest
that the mechanism of Hcy-thiolactone-induced neurotoxicity involves N-
homocysteinylation of brain proteins. Although in this experimental model Hcy is
also generated, postinjection Hcy levels are not significantly different in Pon1 /
and Pon1 +/+ mice and thus do not explain the increased toxicity in Pon1 /
animals. Taken together, the experiments with Pon1-null mouse model provide
the first direct evidence that Hcy-thiolactone, rather than Hcy itself, is neurotoxic
in vivo [140].
Human PON1 has genetic polymorphisms, e.g., PON1-M55L and PON1-
R192Q, which affect PON1 function [265, 266], including Hcy-thiolactonase
activity [152, 261]. For example, high Hcy-thiolactonase activity is associated
with PON1-L55 and PON1-R192 alleles, whereas low Hcy-thiolactonase activity
is associated with PON1-M55 and PON1-Q192 alleles [152, 261]. Purified serum
PON1-R192 allozyme has 2.5-fold higher Hcy-thiolactonase activity than the
PON1-Q192 allozyme [267], which explains the association of high activity
with PON1-R192 allele.
However, several studies have found that PON1 phenotype (Hcy-thiolactonase
or paraoxonase activity) is a predictor of cardiovascular disease, but the PON1-
R192Q or PON1-M55L genotypes are not [255, 265, 266, 268, 269]. For example,
Hcy-thiolactonase activity is found to be significantly lower in a group of 128 coro-
nary artery disease patients with angiographically confirmed atherosclerotic
lesions, compared to a control group of 142 individuals who have no lesions
[255]. A negative correlation is found between the severity of atherosclerotic
lesions and Hcy-thiolactonase activity in the patients. Moreover, the natural Hcy-
thiolactonase activity is a more significant predictor of the disease than the artificial
paraoxonase activity [255].
Furthermore, Hcy is a negative regulator of Pon1 expression in mice [270],
whereas Hcy-thiolactonase activity of PON1 is negatively correlated with plasma
Hcy in humans [261]. Negative effects of Hcy on PON1 expression or activity most
likely contribute to the proatherogenic role of Hcy [256, 257].