Applied nutritional investigationQuercetin reduces serum homocysteine level in rats fed a methionine-enriched diet
Introduction
Homocysteine (Hcy), one of thiol-containing amino acids, is derived from the methionine (Met) metabolism. Two different pathways are involved in its metabolism. The first is remethylation, in which Hcy is recycled to methionine under the catalysis of methionine synthase or betaine-homocysteine methyltransferase (BHMT). The second is transsulfuration, in which Hcy is condensed with serine to form cystathionine under the catalysis of cystathionine-beta-synthase (CBS). The cystathionine is subsequently hydrolyzed to form cysteine (Cys), which is required for glutathione (GSH) synthesis or decomposed finally to form taurine [1], [2], [3].
It has been reported that elevated plasma Hcy concentration is an important risk factor for vascular diseases [4], [5], [6]. One of the possible mechanisms is associated with increased lipid peroxidation. It is proposed that the thiol group of Hcy undergoes auto-oxidation in vivo and generates reactive oxygen species. Consequently, oxidative stress results and leads to the damage of vascular endothelial cells [7], [8]. Some evidences showed that lowering Hcy by nutrition interventions might offer preventive or therapeutic benefits against cardio- and cerebrovascular diseases, although controversy still exists [9], [10], [11], [12], [13], [14]. Several dietary factors, including folate, vitamins B6 and B12, and betaine have been demonstrated to be effective in decreasing plasma Hcy level [10], [11], [12], [13], [14]. However, possible side effects of high doses of B vitamins on atherosclerosis have been hypothesized [15]. Therefore, it is necessary to seek new alternatives in treating hyperhomocysteinemia. Recently, it was reported that catechin, one of the main components in teas, also was effective in reducing plasma Hcy levels in mice fed a Met-enriched diet [16]. Quercetin, a common member of the flavonoids family, is well known for its antioxidant, antiinflammatory, antidiabetic, and cardioprotective actions and is similar to catechin in chemical structure [17], [18], [19], [20], [21]. Previously, a study conducted in our laboratory demonstrated that the Bhmt gene, which is known to code for BHMT in Met metabolism, was downregulated, whereas the Cth gene encoding for cystathionine gamma-lyase was upregulated in expression by quercetin treatment in rats [22]. Therefore, we hypothesize that quercetin may have potential to combat hyperhomocysteinemia.
The present study investigated the effects of quercetin on Hcy metabolism in rats fed a Met-enriched diet and probed into the mechanisms possibly involved. Additionally, the changes of hepatic antioxidant status after quercetin administration also were measured in order to validate the antioxidant action of quercetin.
Section snippets
Chemicals
L-Met, Hcy, 4-chloro-7-sulfobenzofurazan ammonium salt (SBD-F), GSH, N-acetyl-Cys, L-Cys, 2,4,6-tripyridy-s-triazine (TPTZ), β-glucuronidase type H-2 (from Helix pomatia), quercetin, and isorhamnetin were obtained from Sigma-Aldrich, Inc (St Louis, MO, USA). All other chemicals were of the highest grade available.
Animals and experimental protocol
Forty male Wistar rats, weighing 177 g to 198 g, were purchased from the Laboratory Animal Center (Chinese Academy of Military Medical Science, Beijing, P.R. China) and housed
Dietary intake, body weight gain, and ratio of liver weight to body weight
No significant difference was found in dietary intake among the five groups during experimental period. The body weight gain in the rats fed the 1.0% Met and 2.5% quercetin-supplemented diet decreased significantly compared with those fed the control, 1.0% Met, 1.0% Met and 0.1% quercetin, or 1.0% Met and 0.5% quercetin-supplemented diets (P < 0.05; Table 1). The ratio of liver weight to body weight was significantly increased in the rats fed the 1.0% Met and 2.5% quercetin-supplemented diet
Discussion
In the present study, hypercysteinemia was induced successfully in rats fed a 1.0% Met-supplemented diet, which was in agreement with our previous study [32]. It also was shown that quercetin treatment led to a significant increase in serum contents of quercetin and its metabolites in a dose-dependent manner, confirming that quercetin is bioavailable significantly after feeding. It has been demonstrated that quercetin is extensively metabolized in the gut and liver after absorption and occurs
Conclusions
This study demonstrates that quercetin supplementation is effective in attenuating the increase of serum Hcy level as induced by a Met-enriched diet in rats. The possible mechanism is associated with improved transsulfuration of Hcy. However, an excess intake of quercetin is not beneficial in terms of antioxidant status in rats subjected to a Met-enriched diet. Further study is in progress in our laboratory to explore the detailed mechanisms for the action of quercetin on hypercysteinemia.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Project No 30901184).
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All authors participated in the design, interpretation of the studies, and analysis of the data and review of the manuscript. Bin Meng, Weina Gao, and Changjiang Guo wrote the manuscript. All authors approved the final version of manuscript. Bin Meng and Weina Gao contributed equally.