Effects of betaine supplementation on hepatic metabolism of sulfur-containing amino acids in mice

Background/Aims

We previously reported that acute betaine treatment induced significant changes in the hepatic glutathione and cysteine levels in mice and rats. The present study was aimed to determine the effects of dietary betaine on the metabolism of sulfur-containing amino acids.

Methods/Results

Male mice were supplemented with betaine (1%) in drinking water for up to 3 weeks. Changes in hepatic levels of major sulfur amino acid metabolites and products were stabilized after 2 weeks of betaine supplementation. Betaine intake increased methionine, S-adenosylmethionine, and S-adenosylhomocysteine levels significantly, but homocysteine and cystathionine were reduced. Methionine adenosyltransferase activity was elevated to three-fold of control. Cysteine catabolism to taurine was inhibited as evidenced by a decrease in cysteine dioxygenase activity and taurine levels in liver and plasma. Despite the significant changes in the transsulfuration reactions, neither hepatic cysteine nor glutathione was altered. Betaine supplementation decreased the hepatotoxicity induced by chloroform (0.5 ml/kg, ip) significantly.

Conclusions

Betaine supplementation enhances recycling of homocysteine for the generation of methionine and S-adenosylmethionine while reducing its utilization for the synthesis of cystathionine and cysteine. However, the hepatic levels of cysteine or glutathione are not affected, most probably due to the depression of taurine generation from cysteine.

Introduction

In mammals, the liver plays a central role in the metabolism of sulfur-containing amino acids because nearly one-half of the daily methionine intake is metabolized there [1]. Methionine metabolism occurs primarily via the transsulfuration pathway, which results in transfer of methionine sulfur to serine to form cysteine (Fig. 1). The first step in transsulfuration reactions is the formation of S-adenosylmethionine (SAM) that is catalyzed by methionine adenosyltransferase (MAT). SAM serves as the methyl donor for various biological methylation reactions, and the co-product, S-adenosylhomocysteine (SAH), is hydrolyzed to yield homocysteine that is either remethylated to methionine or condensed with serine into cystathionine. The transsulfuration of homocysteine to cysteine via cystathionine is mediated by the consecutive actions of cystathionine β-synthase (CβS) and cystathionine γ-lyase (CγL). Cysteine is irreversibly metabolized in liver to yield either taurine, inorganic sulfate, or glutathione (GSH). Cysteine dioxygenase (CDO) catalyzes the oxidation of this amino acid to cysteine sulfinate that is mainly converted to taurine via hypotaurine by the activity of cysteine sulfinate decarboxylase (CDC). Synthesis of GSH is mediated by γ-glutamylcysteine ligase (GCL) and GSH synthetase, consecutively.

Betaine, an oxidative metabolite of choline, is involved in the synthesis of methionine from homocysteine in liver. This reaction, catalyzed by betaine homocysteine methyltransferase (BHMT), has an important role in the maintenance of hepatic methionine, especially when the dietary intake of this amino acid is limited [2]. It was shown that betaine intake increased the hepatic SAM concentrations in experimental animals [3], and also reduced the homocysteine levels in human with homocystinuria [4]. Recently, it has been demonstrated that betaine supplementation prevents a rise in plasma homocysteine concentrations after methionine intake in persons with normal to mildly elevated homocysteine levels [5], [6]. But little published information is available concerning its effect on the transsulfuration reactions beyond homocysteine.

Our previous study indicated that acute betaine treatment to mice resulted in time-dependent changes in the hepatotoxicity induced by chloroform, which was associated with alterations in the hepatic GSH levels [7]. Recently, we have demonstrated that the changes in hepatic GSH in animals treated with betaine may be explained by its effect on the cysteine availability in liver [8]. In that study an acute dose of betaine rapidly enhanced metabolic reactions in the methionine cycle, but inhibited cystathionine synthesis and hepatic uptake of cysteine, leading to a decrease in the cysteine availability for GSH synthesis. Reduction in GSH was reversed slowly with the induction of cysteine synthesis and GCL activity. However, the effects of repeated betaine treatment on hepatic cysteine and GSH remained unknown. Inhibition of the transsulfuration reactions from homocysteine to cysteine may lead to a decrease in the synthesis of GSH, which would produce an important impact on normal biochemistry and physiology of mammals. Therefore, it was of significance to ascertain the changes in the hepatic metabolism of sulfur amino acids in animals supplemented with betaine.