Homocysteine threshold value based on cystathionine beta synthase and paraoxonase 1 activities in mice.
BACKGROUND
Hyperhomocysteinaemia is a metabolic disorder associated with the development of premature atherosclerosis. Among the determinants which predispose to premature thromboembolic and atherothrombotic events, serum activity of paraoxonase 1, mainly synthesized in the liver, has been shown to be a predictor of cardiovascular disease and to be negatively correlated with serum homocysteine levels in human. Even though treatments of hyperhomocysteinaemic patients ongoing cardiovascular complications are commonly used, it still remains unclear above which homocysteine level a preventive therapy should be started.


METHODS
In order to establish a threshold of plasma homocysteine concentration we have analyzed the hepatic cystathionine beta synthase and paraoxonase 1 activities in a moderate to intermediate murine model of hyperhomocysteinaemia. Using wild type and heterozygous cystathionine beta synthase deficient mice fed a methionine enriched diet or a control diet, we first studied the link between cystathionine beta synthase and paraoxonase 1 activities and plasma homocysteine concentration.


RESULTS
Among the animals used in this study, we observed a negative correlation between plasma homocysteine level and cystathionine beta synthase activity (rho=-0.52, P=0.0008) or paraoxonase 1 activity (rho=-0.49, P=0.002). Starting from these results, a homocysteine cut-off value of 15 microm has been found for both cystathionine beta synthase (P=0.0003) and paraoxonase 1 (P=0.0007) activities.


CONCLUSIONS
Our results suggest that both cystathionine beta synthase and paraoxonase 1 activities are significantly decreased in mice with a plasma homocysteine value greater than 15 microm. In an attempt to set up preventive treatment for cardiovascular disease our results indicate that treatments should be started from 15 microm of plasma homocysteine.
Hamelet
J
J
EA 3508, Université Paris Diderot-Paris 7, and Hôpital Européen Georges Pompidou, Service de Biochemie, Paris, France.
Aït-Yahya-Graison
E
E
Matulewicz
E
E
Noll
C
C
Badel-Chagnon
A
A
Camproux
A-C
AC
Demuth
K
K
Paul
J-L
JL
Delabar
J M
JM
Janel
N
N
D000818:Animals; D043303:Aryldialkylphosphatase / Q000378:metabolism*; D003541:Cystathionine beta-Synthase / Q000378:metabolism*; D004195:Disease Models, Animal; D006710:Homocysteine / Q000097:blood*; D020138:Hyperhomocysteinemia / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice
D006710:Homocysteine; D043303:Aryldialkylphosphatase; D003541:Cystathionine beta-Synthase