Kim Sang K, Choi Kwon H, Kim Young C
College of Pharmacy, Seoul National University, San 56-1 Shinrim-Dong, Kwanak-Ku, Seoul, South Korea.
Biochem Pharmacol. 2003 May 1;65(9):1565-74. doi: 10.1016/s0006-2952(03)00115-1.
Alterations of hepatic glutathione level by betaine were observed previously. In this study effects of betaine administration (1000 mg/kg, i.p.) on S-amino acid metabolism in rats and mice were investigated. Hepatic glutathione level decreased rapidly followed by marked elevation in 24 hr. Concentrations of S-adenosylmethionine, S-adenosylhomocysteine, and methionine were increased whereas cystathionine decreased significantly, suggesting that homocysteine generated in the methionine cycle is preferentially remethylated to methionine rather than being utilized for synthesis of cysteine. Hepatic cysteine concentration declined immediately, but plasma cysteine increased. Effect of betaine on hepatic cysteine uptake was estimated from the difference in cysteine concentration in major blood vessels connected to liver. Cysteine concentration either in the portal vein or abdominal aorta was not altered, however, a significant increase was noted in the hepatic vein, indicating that hepatic uptake of cysteine was decreased by betaine treatment. Activities of glutamate cysteine ligase, cystathionine beta-synthase, and cystathionine gamma-lyase were elevated in 24 hr. Pretreatment with propargylglycine, an irreversible inhibitor of cystathionine gamma-lyase, did not abolish the betaine-induced reduction of hepatic glutathione in 4 hr, however, the elevation at t=24 hr was blocked completely. In conclusion the present results indicate that betaine administration induces time-dependent changes on hepatic metabolism of S-amino acids. Betaine enhances metabolic reactions in the methionine cycle, but inhibits cystathionine synthesis and cysteine uptake, leading to a decrease in supply of cysteine for glutathione synthesis. Reduction in glutathione is subsequently reversed due to induction of cysteine synthesis and glutamate cysteine ligase activity.
先前已观察到甜菜碱对肝脏谷胱甘肽水平的影响。在本研究中，研究了给予大鼠和小鼠甜菜碱（1000mg/kg，腹腔注射）对S-氨基酸代谢的影响。肝脏谷胱甘肽水平迅速下降，随后在24小时内显著升高。S-腺苷甲硫氨酸、S-腺苷同型半胱氨酸和甲硫氨酸的浓度升高，而胱硫醚显著降低，这表明甲硫氨酸循环中产生的同型半胱氨酸优先重新甲基化为甲硫氨酸，而不是用于合成半胱氨酸。肝脏半胱氨酸浓度立即下降，但血浆半胱氨酸增加。根据与肝脏相连的主要血管中半胱氨酸浓度的差异估算甜菜碱对肝脏半胱氨酸摄取的影响。门静脉或腹主动脉中的半胱氨酸浓度未发生改变，然而，肝静脉中的半胱氨酸浓度显著升高，表明甜菜碱处理降低了肝脏对半胱氨酸的摄取。谷氨酸半胱氨酸连接酶、胱硫醚β-合酶和胱硫醚γ-裂解酶的活性在24小时内升高。用炔丙基甘氨酸（一种胱硫醚γ-裂解酶的不可逆抑制剂）预处理，在4小时内并未消除甜菜碱诱导的肝脏谷胱甘肽减少，然而，在t=24小时时的升高被完全阻断。总之，目前的结果表明，给予甜菜碱会诱导肝脏S-氨基酸代谢的时间依赖性变化。甜菜碱增强甲硫氨酸循环中的代谢反应，但抑制胱硫醚合成和半胱氨酸摄取，导致用于谷胱甘肽合成的半胱氨酸供应减少。随后，由于半胱氨酸合成和谷氨酸半胱氨酸连接酶活性的诱导，谷胱甘肽的减少得以逆转。
