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© 2006 American Society for Nutrition J. Nutr. 136:2797-2802, November 2006

Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Dietary Eritadenine Suppresses Guanidinoacetic Acid-Induced Hyperhomocysteinemia in Rats1

Shin-ichiro Fukada, Minoru Setoue, Tatsuya Morita and Kimio Sugiyama*

Department of Applied Biological Chemistry, Faculty of Agriculture, Shizuoka University, 836 Ohya, Shizuoka 422–8529, Japan

* To whom correspondence should be addressed. E-mail: acksugi{at}agr.shizuoka.ac.jp.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
We assessed the effect of eritadenine, a hypocholesterolemic factor isolated from the edible mushroom Lentinus edodes, on plasma homocysteine concentration using methyl-group acceptor-induced hyperhomocysteinemic rats. Male Wistar rats were fed a control diet or diets supplemented with a methyl-group acceptor or a precursor of methyl-group acceptor. Diets were supplemented with guanidinoacetic acid (GAA) at 2.5, 5, 7.5, and 10 g/kg, nicotinic acid (NiA) or ethanolamine (EA) at 5 and 10 g/kg, or glycine at 25 and 50 g/kg, and the rats were fed for 10 d (Expt. 1). Plasma total homocysteine concentration was increased 255 and 421% by 5 and 10 g/kg GAA, respectively, and 39 and 58% by 5 and 10 g/kg NiA, respectively, but not by EA or glycine. GAA supplementation dose-dependently decreased the hepatic S-adenosylmethionine (SAM) concentration and the activity of cystathionine ß-synthase (CBS) and increased the hepatic S-adenosylhomocysteine (SAH) and homocysteine concentrations. In another study in which rats were fed 5 g/kg GAA-supplemented diet for 1–10 d, plasma homocysteine and the other variables affected in Expt. 1 were affected in rats fed the GAA-supplemented diet (Expt. 2). We investigated the effect of supplementation of 5 g/kg GAA-supplemented diet with eritadenine (50 mg/kg) on plasma homocysteine concentration (Expt. 3). Eritadenine supplementation significantly suppressed the GAA-induced increase in plasma homocysteine concentration. Eritadenine also restored the decreased SAM concentration and CBS activity in the liver, whereas it further increased hepatic SAH concentration, suggesting that eritadenine might elicit its effect by both slowing homocysteine production and increasing cystathionine formation. The results confirm that GAA is a useful compound to induce experimental hyperhomocysteinemia and indicate that eritadenine can effectively counteract the hyperhomocysteinemic effect of GAA.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Homocysteine is a usual amino acid that is formed by the hydrolysis of S-adenosylhomocysteine (SAH)2 in the metabolism of methionine (Fig. 1). Elevated plasma homocysteine concentration is an independent risk factor for cardiovascular disease (1–5). Associations of elevated plasma homocysteine with Alzheimer's disease and cognitive impairment have also been reported (6,7). In humans, normal plasma total homocysteine concentrations are in the range of 5–15 µmol/L, and an increase of 5 µmol/L in this amino acid concentration is associated with an increased risk of 60% for men and 80% for women of coronary heart disease (2). It has been shown that plasma homocysteine concentration is influenced by various factors (1–4). For instance, deficiencies of some vitamins such as folate, vitamin B-6, and B-12 lead to hyperhomocysteinemia due to impaired metabolism of homocysteine. Genetic defects of several enzymes that are involved in the metabolism of homocysteine also bring about hyperhomocysteinemia. Furthermore, advanced age, male sex, impaired renal function, and high alcohol intake are known to be associated with higher plasma homocysteine concentrations.


Figure 1
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  		Figure 1  Methionine metabolism. DMG, N,N-dimethylglycine; NiANH2, nicotinamide; THF, tetrahydrofolate. Enzymes: GAA N-methyltransferase (EC 2.1.1.2); nicotinamide N-methyltransferase (EC2.1.1.1); PE N-methyltransferase (EC 2.1.1.17); and glycine N-methyltransferase (EC 2.1.1.20).

 
To investigate the regulation of plasma homocysteine concentration, appropriate animal models of hyperhomocysteinemia are needed. For this purpose, hyperhomocysteinemia induced by methionine loading or folate-deficient diet has often been used (8,9). On the other hand, it has been shown that some direct methyl-group acceptors for the methyl-group of S-adenosylmethionine (SAM) or indirect methyl-group acceptors, which are the precursor of direct methyl-group acceptors, increased plasma homocysteine concentration (10–12). Basu and Mann (10) have shown that dietary supplementation with nicotinic acid (NiA), which is metabolized to nicotinamide and can accept a methyl-group via nicotinamide N-methyltransferase, increased plasma homocysteine concentration in rats. An increase in plasma homocysteine concentration by dietary supplementation with guanidinoacetic acid (GAA), which is the substrate of GAA N-methyltransferase, was also demonstrated in rats (11). Furthermore, it was shown that plasma homocysteine concentration was considerably lower in phosphatidylethanolamine (PE) N-methyltransferase knockout mice than in control mice, suggesting that PE N-methylation is a system to raise plasma homocysteine (12). These results suggest that methyl-group acceptors or precursors might be useful to induce a novel type of hyperhomocysteinemia, although optimal experimental conditions to induce obvious hyperhomocysteinemia and the mechanism of the hyperhomocysteinemia have not yet been fully defined.

Eritadenine is a hypocholesterolemic factor isolated from the mushroom Lentinus edodes (Shiitake in Japanese), which is the most popular edible mushroom in Japan (13,14). We have previously reported that eritadenine could affect the metabolism of not only cholesterol but also phospholipids and fatty acids when added to the diet in rats (15–18). All of the effects of eritadenine were thought to arise from the inhibition of SAH hydrolase. This feature of eritadenine led us to consider the possibility that eritadenine may counteract the effect of methyl-group acceptors.

In this study, we first investigated the effects of dietary supplementation with direct methyl-group acceptors such as GAA and glycine or indirect methyl-group acceptors such as NiA and ethanolamine (EA) on plasma homocysteine concentration in rats to clarify what type of methyl-group acceptor is suitable to induce obvious experimental hyperhomocysteinemia. Because GAA was found to induce severe hyperhomocysteinemia, the time-dependent effect of GAA was also investigated. Using GAA-induced hyperhomocysteinemic rats, we assessed the effect of eritadenine on plasma homocysteine concentration.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Chemicals. GAA and EA hydrochloride were purchased from Sigma-Aldrich, and NiA and glycine were purchased from Wako Pure Chemical. All other chemicals were purchased from Sigma-Aldrich or Wako and were of analytical grade. Eritadenine was kindly supplied by Tanabe Seiyaku. Mineral and vitamin mixtures (AIN-93G) and other ingredients were purchased from Oriental Yeast, Wako, or Nacalai Tesque.

    Animals and diets. Six-wk-old male rats (120–140 g) of the Wistar strain were obtained from Japan SLC. They were individually housed in hanging stainless-steel wire cages kept in an isolated room at a controlled temperature (23–25°C) and humidity (40–60%). Lighting was maintained on a 12-h cycle (lights on from 0700 to 1900). Before starting the experiments, all rats were acclimated to the facility for 4 or 5 d and given free access to water and a diet containing casein at a level of 250 g/kg, which was the same as the control diet described below. The control diet consisted of the following ingredients (g/kg): casein, 250; corn starch, 432.5; sucrose, 200; corn oil, 50; 35; vitamin mixture (AIN-93G) (19), mineral mixture (AIN-93G) (19), 10; choline bitartrate, 2.5; and cellulose, 20. In Expt. 3, choline bitartrate was introduced into the diet at a higher level of 5 g/kg to avoid the development of fatty liver. Supplements were added to the diet at the expense of starch. Three experiments were conducted in this study. In Expt. 1, rats were given free access to the control diet or diets supplemented with graded levels of GAA, NiA, EA, or glycine for 10 d. The effect of NiA was assessed with a separate control group at a different time from the effects of GAA, EA, and glycine. The supplementation levels were as follows; 2.5, 5, 7.5, and 10 g/kg for GAA (molecular wt, 117.1), 5 and 10 g/kg for NiA (molecular wt, 123.1) and EA (molecular wt, 61.1), and 25 and 50 g/kg for glycine (molecular wt, 75.1). In Expt. 2, rats were given free access to the control diet for 10 d or the diet supplemented with 5 g/kg GAA for 1, 5, and 10 d; the rats fed the GAA-supplemented diet for 1 and 5 d were previously fed the control diet for 9 and 5 d, respectively. In Expt. 3, rats were given free access to the control diet or the GAA-supplemented (5 g/kg) diet with or without eritadenine (50 mg/kg) for 10 d. The dose of eritadenine was sufficient to bring about a maximal effect on the metabolism of lipids, as shown previously (20). The experimental plan of this study was approved by the Laboratory Animal Care Committee of the Faculty of Agriculture, Shizuoka University.

    Tissue collection and fractionation. Rats were killed by decapitation to obtain blood and livers between 1000 and 1030 h without prior food deprivation. Blood plasma was separated from the heparinized whole blood by centrifugation at 2000 x g; 15 min at 4°C and stored at –80°C until used for determination of the concentrations of total homocysteine. After the collection of blood, the whole liver was quickly removed, rinsed in ice-cold saline, blotted on filter paper, cut into 2 portions, weighed, and quickly frozen in liquid nitrogen and stored at –80°C until analyses. The homogenization of the liver and the centrifugation of the homogenate for the analyses of the concentrations of methionine metabolites and enzyme activity were conducted according to the methods described previously (17).

    Biochemical analysis. The concentrations of total homocysteine and cysteine in the plasma and liver were measured by HPLC essentially according to Durand et al. (21) using L-cysteine as a standard. The concentrations of SAM and SAH in the liver were measured by HPLC according to Cook et al. (22) with slight modifications as described previously (15). The activity of cystathionine ß-synthase (CBS) in the liver was measured according to Mudd et al. (23) but using HPLC for the assay of the reaction product, cystathionine, according to Einarsson et al. (24). The protein concentration was measured according to Lowry et al. (25) using bovine serum albumin as a standard.

    Statistical analysis. Data are expressed as the mean ± SEM. In Expt. 1, the effect of each compound was statistically analyzed separately, where the same control group was used for GAA, EA, and glycine, but not for NiA. Data were analyzed by a 1-way ANOVA, and the difference between mean values was tested by the Bonferroni/Dunn multiple range test (26) when the F-value was significant. When variances among the groups were not homogeneous, some data were logarithmically transformed before ANOVA. Statistical analysis was performed using Mac Toukei-Kaiseki version 1.5 software (Esumi).


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Induction of hyperhomocysteinemia by methyl-group acceptors (Expt. 1). Dietary supplementation with direct or indirect methyl-group acceptors did not depress the body wt gain of rats, except for 10 g/kg NiA; 49 ± 1 vs. 45 ± 2 g/10 d in the control group and NiA group, respectively (P < 0.05, n = 6). Food intake was lower in rats fed GAA at 5 (117 ± 3, g/10 d) and 7.5 g/kg (116 ± 2) compared with controls (126 ± 4) (P < 0.05). The relative liver weight (g/100 g body wt) was lower in rats fed GAA at 2.5 (4.41 ± 0.04), 5 (4.26 ± 0.06), and 7.5 g/kg (4.21 ± 0.04) compared with controls (4.69 ± 0.10) (P < 0.05). Supplementation with GAA and NiA, but not EA and glycine, significantly increased plasma total homocysteine concentration (Fig. 2). At the levels of 5 and 10 g/kg, GAA increased plasma homocysteine concentration to levels 255 and 421% higher, respectively, than the concentrations in the control group, whereas NiA increased plasma homocysteine concentration only 39 and 58% higher, respectively, than the concentration in the control group (P < 0.05). The concentration of hepatic SAM was decreased by GAA supplementation in a dose-dependent manner, whereas the concentrations of hepatic SAH and homocysteine were increased by GAA in a dose-dependent manner (Fig. 3A,B,D). Consequently, the SAM:SAH ratio was significantly decreased by GAA (Fig. 3C). The activity of hepatic CBS was significantly decreased by GAA in a dose-dependent manner (Fig. 3E).


Figure 2
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  		Figure 2  Effects of dietary supplementation with GAA, NiA, EA, or glycine on plasma homocysteine concentration in rats (Expt. 1). Values are means ± SEM, n = 5 or 6. Means in a panel without a common letter differ, P < 0.05.

 

Figure 3
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  		Figure 3  Effects of dietary supplementation with GAA on the concentrations of methionine metabolites (A–D) and CBS activity (E) in the liver of rats (Expt. 1). Values are means ± SEM, n = 5 or 6. Means in a panel without a common letter differ, P < 0.05.

 
    Effect of feeding period of GAA-supplemented diet (Expt. 2). The concentration of plasma homocysteine significantly increased after feeding the diet supplemented with GAA at a level of 5 g/kg for only 1 d and reached a plateau (Fig. 4A). The concentration of hepatic SAM and the activity of CBS significantly decreased after feeding the GAA diet for 1 d and reached nadirs (Fig. 4B,F). The hepatic SAH concentration significantly increased after feeding the GAA diet for 1 d and reached a plateau after 5 d (Fig. 4C). The SAM:SAH ratio significantly decreased after feeding the GAA diet for 1 d and reached a nadir after 5 d (Fig. 4D). The hepatic homocysteine concentration significantly increased after feeding the GAA diet for 5 d and reached a plateau (Fig. 4E).


Figure 4
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  		Figure 4  Indicators of methionine metabolism in rats fed 5 g/kg GAA diets for 1–10 d (Expt. 2). Values are means ± SEM, n = 6. Means in a panel without a common letter differ, P < 0.05. Data in the panel E were logarithmically transformed before ANOVA.

 
    Effect of eritadenine on GAA-induced hyperhomocysteinemia (Expt. 3). Eritadenine supplementation did not affect growth, food intake, and relative liver weight (data not shown). The increase in plasma homocysteine concentration induced by dietary supplementation with GAA at a level of 5 g/kg was almost completely suppressed by concurrent supplementation with eritadenine at a level of 50 mg/kg (Fig. 5A). The GAA-induced decrease in hepatic SAM concentration was recovered to the level of the control group by eritadenine, whereas hepatic SAH concentration was further increased by eritadenine (Fig. 5B,C). The GAA-induced decrease in the SAM:SAH ratio was not altered by eritadenine (Fig. 5D). The activity of hepatic CBS was increased by eritadenine to a level higher than that of the control group (Fig. 5F).


Figure 5
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  		Figure 5  Effects of dietary supplementation with eritadenine in combination with GAA on plasma homocysteine concentration (A), hepatic concentrations of methionine metabolites (B–E), and hepatic CBS activity (F) in rats (Expt. 3). Values are means ± SEM, n = 6. Means in a panel without a common letter differ, P < 0.05. Data in panel E were logarithmically transformed before ANOVA. C, Normal diet containing casein at a level of 250 g/kg; CG, C + GAA (5 g/kg); CGE, CG + eritadenine (50 mg/kg).

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
The results obtained here clearly demonstrate that GAA has a substantial hyperhomocysteinemic effect when added to the diet in rats. The results confirm the previous finding by Stead et al. (11) that GAA administration increased plasma homocysteine concentration; they have shown that feeding rats with a GAA-supplemented (3.6 g/kg) diet for 2 wk increased plasma homocysteine concentration by ~50%. We demonstrated that GAA could increase plasma homocysteine concentration by severalfold when added to the diet at higher levels. We also found that GAA could increase plasma homocysteine concentration within a short time, even only 1 d, after feeding the GAA-supplemented diet. Dietary supplementation with NiA also resulted in a significant increase in plasma homocysteine concentration, as found in previous studies (10,27). However, the potency of the homocysteine-increasing effect of NiA, i.e., 39 and 58% increases at 5 and 10 g/kg, respectively, appears to be small compared with the potency of the effect of GAA, i.e. 255 and 421% increases at 5 and 10 g/kg, respectively (Fig. 2). Thus, our results support that GAA is an effective compound to induce experimental hyperhomocysteinemia and suggest that GAA supplementation at ~5 g/kg and feeding for 5–10 d might be adequate conditions to induce intermediate (total homocysteine, 30–100 µmol/L) (28) hyperhomocysteinemia.

The concentration of hepatic homocysteine thought to reflect plasma homocysteine concentration (29) is determined by the rates of the following processes: production of homocysteine from SAH or its precursor SAM, formation of cystathionine from homocysteine and serine, remethylation of homocysteine to methionine, and export of homocysteine into blood plasma. In this study, we provided several data to elucidate the mechanism by which GAA induced hyperhomocysteinemia. The finding that hepatic SAM and SAH concentrations were inversely affected by GAA in a dose-dependent manner (Fig. 3) supports the view that loading of methyl-group acceptors might accelerate the metabolism of SAM to SAH and thereby increase the production of homocysteine from SAH (11,30). The strong effect of GAA on the SAM:SAH ratio is consistent with the estimation by Mudd et al. (31,32) that creatine synthesis in humans comprises the major part (~75%) of SAM consumption and suggests that the activity of GAA N-methyltransferase might be higher than the activities of other methyltransferases. On the other hand, the relatively weak effect of NiA on plasma homocysteine concentration may be due to lower activity to convert NiA to nicotinamide (33) and/or to methylate nicotinamide in the liver. Noga et al. (12) and Jacobs et al. (34) have shown that the PE N-methylation system is an important source of plasma homocysteine in mice. Consistent with this, it has been shown that feeding a diet rich in PE considerably increased plasma homocysteine concentration in mink (35). Because EA is a substrate of PE synthesis via the cytidine diphospho-EA pathway, dietary supplementation with EA increases hepatic PE concentration (17). Nevertheless, no enhancing effect of dietary EA on plasma homocysteine concentration was detected in our study. Although the basis for this phenomenon is currently uncertain, one possible explanation is that increased PE derived from dietary EA in the liver, probably beyond some range, may not further augment methylation demand. Because glycine N-methyltransferase is abundant in the liver and serves to regulate the relative levels of SAM and SAH (36,37), we investigated whether glycine supplementation could enhance plasma homocysteine concentration. The results showed that glycine had no effect on plasma homocysteine concentration even at a high level (50 g/kg). One possible explanation for the inability of glycine to enhance plasma homocysteine concentration is that glycine was converted to serine, one of the substrates of cystathionine synthesis, and thereby stimulated the removal of homocysteine.

Stead et al. (11) have shown that hepatic CBS activity tended to be higher in GAA-fed rats than in control rats. Finkelstein et al. (38) have also demonstrated that single intraperitoneal injection with nicotinamide increased hepatic CBS activity 16 h or more after the injection in rats, and they supposed that an increased synthesis of cystathionine would provide for the removal of SAH and homocysteine derived from SAM-dependent methylation of nicotinamide. In contrast, we showed that the CBS activity was decreased by dietary supplementation with GAA in a dose-dependent manner. The reason for the discrepancy in the response of CBS activity to GAA or nicotinamide between the results by Stead et al. (11) or Finkelstein et al. (38) and our results is uncertain. The decreased CBS activity in GAA-fed rats observed in our study might be explained in part by the decrease in hepatic SAM concentration, because CBS is activated by SAM allosterically (39). In fact, there was a significant correlation between the mean values of CBS activity and hepatic SAM concentration in Expt. 1 (Fig. 3A,E); r = 0.966, P < 0.01. Thus, our results suggest that GAA might increase hepatic homocysteine concentration by at least 2 mechanisms: accelerated metabolism of SAM to SAH by directly accepting the methyl-group of SAM and suppressed formation of cystathionine due to a decrease in CBS activity. In addition, the possibility that GAA decreased homocysteine remethylation and thereby increased plasma homocysteine concentration cannot be excluded, although this remains to be examined experimentally.

Eritadenine is an adenosine analogue isolated from the popular edible mushroom L. edodes as a hypocholesterolemic factor (13,14). Eritadenine also exists in the mushroom Agaricus bisporus (champignon) but to a lesser extent (40). Eritadenine, as well as many other adenosine analogs, is a potent inhibitor of SAH hydrolase (EC 3.3.1.1) (41,42). We have previously reported that dietary supplementation with eritadenine led to a decrease in phosphatidylcholine biosynthesis via PE N-methylation and a resultant increase in hepatic PE concentration (15,17,43). Eritadenine also suppressed the metabolism of linoleic acid due to a decrease in {Delta}6-desaturase activity (17,18,20). Although the mechanism by which eritadenine elicits its hypocholesterolemic action has not yet been fully elucidated, it is likely that a wide range of effects of eritadenine on lipid metabolism are initiated by the inhibition of SAH hydrolase and a resultant increase in SAH concentration (18). In addition to the effects on lipid metabolism, this study clearly demonstrated that eritadenine could effectively suppress GAA-induced hyperhomocysteinemia. This finding appears to be useful in considering the nutritional and physiological function of certain mushrooms such as L. edodes and A. bisporus. The effect of eritadenine might be accounted for at least by the following: slowdown of homocysteine production from SAH, increase in CBS activity, and suppression of GAA N-methyltransferase. Because eritadenine is a potent inhibitor of SAH hydrolase, it is reasonable to assume that eritadenine delayed the production of homocysteine from SAH. The increase in CBS activity in rats fed the eritadenine-supplemented diet might be partially explained by the restoration of hepatic SAM concentration, but this does not explain why the level of CBS activity in eritadenine-fed rats was significantly higher than that in the control rats. It was shown that the activity of CBS was activated by SAH in addition to SAM (44), although the relative potency of these compounds was not estimated. Hence, it is possible that a higher concentration of hepatic SAH may also contribute to the increase in CBS activity in eritadenine-fed rats. On the other hand, the possibility that increased SAH concentration in eritadenine-fed rats leads to inhibition of GAA N-methyltransferase activity and thereby mitigates the effect of GAA cannot be ruled out, because SAH is a potent inhibitor of GAA methyltransferase as well as other methyltransferases (45).

Some adenosine deaminase inhibitors, such as 2'-deoxycoformycin, decreased plasma homocysteine concentration in acute lymphoblastic leukemia patients (46). This effect appears to be due to the increase in cellular adenosine concentration and resultant inhibition of the hydrolysis of SAH, because intracellular adenosine is thought to be involved in the regulation of SAH hydrolase activity (47). On the other hand, Ueland et al. (48) have reported that injection of mice under normal conditions with the combination of 9-ß-D-arabinofuranosyladenine, a SAH hydrolase inhibitor, plus 2'-deoxycoformycin did not affect homocysteine concentration in several tissues except for the kidney, although these drugs largely increased SAH concentration in all the tissues tested. Unfortunately, they did not measure the effect of the drugs on plasma homocysteine concentration. In a separate study, we found that eritadenine did not decrease plasma homocysteine concentration when added to the normal diet in rats (unpublished data). These observations suggest that SAH hydrolase inhibitors might act to normalize hyperhomocysteinemia rather than to decrease the normal range of plasma homocysteine concentration.


   FOOTNOTES
 
1 Supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Culture, Sports and Technology of Japan. Back

2 Abbreviations used: CBS, cystathionine ß-synthase; EA, ethanolamine; GAA, guanidinoacetic acid; NiA, nicotinic acid; PE, phosphatidylethanolamine; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine. Back

Manuscript received 12 February 2006. Initial review completed 16 March 2006. Revision accepted 23 August 2006.


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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
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