College of Pharmacy, Seoul National University, San 56-1 Shinrim-Dong, Kwanak-Ku, Seoul, South Korea.
Biochimie. 2013 Aug;95(8):1605-10. doi: 10.1016/j.biochi.2013.04.015. Epub 2013 May 10.
It has been known that liver regeneration is accompanied with a profound change in the metabolomics of sulfur-containing substances in liver. However, its physiological significance in the liver regenerative process is still unclear. Our previous work showed that buthioninesulfoximine and phorone, both widely used to deplete intracellular glutathione (GSH) in biological experiments, induced contrasting changes in the sulfur-containing amino acid metabolism in liver. In this study we employed these GSH-depleting agents to evaluate the role of sulfur-containing substances in the early phase of liver regeneration. Male rats treated with buthioninesulfoximine or phorone were subjected to two-thirds partial hepatectomy (PHx). At the doses used, the magnitude of GSH depletion after PHx was comparable, but buthioninesulfoximine administration inhibited the progression of liver regeneration as determined by liver weight increase, elevation of serum alanine aminotransferase activity, and cyclin D1 and proliferating cell nuclear antigen (PCNA) protein expressions, whereas liver recovery was significantly accelerated in the phorone-treated rats, suggesting that the role of GSH in this process is minimal. Hepatic concentrations of methionine, S-adenosylmethionine, cysteine, taurine and GSH were all elevated by PHx. Methionine adenosyltransferase activity was also induced in the remnant liver. Buthioninesulfoximine administration depressed the elevation of S-adenosylmethionine, but increased the catabolism of cysteine to taurine. In contrast, S-adenosylmethionine elevation was augmented whereas cysteine, hypotaurine and taurine were decreased in the phorone-treated rats. PHx elevated hepatic putrescine and spermidine, but lowered spermine concentrations. Buthioninesulfoximine administration increased putrescine further, but decreased spermidine and spermine concentrations. On the contrary, both spermidine and spermine concentrations were elevated in the rats treated with phorone. The results suggest that the availability of S-adenosylmethionine plays a critical role in the progression of liver regeneration via enhancement of polyamine synthesis. These findings raise the possibility that regulating hepatic transsulfuration reactions may be capable of modifying the recovery process after liver injury.
已知肝脏再生伴随着肝脏含硫物质代谢组学的深刻变化。然而，其在肝脏再生过程中的生理意义尚不清楚。我们之前的工作表明，广泛用于生物实验中耗尽细胞内谷胱甘肽 (GSH) 的丁硫氨酸亚砜胺和磷苯，诱导肝脏含硫氨基酸代谢的相反变化。在这项研究中，我们使用这些 GSH 耗竭剂来评估含硫物质在肝再生早期阶段的作用。用丁硫氨酸亚砜胺或磷苯处理的雄性大鼠接受 2/3 部分肝切除术 (PHx)。在使用的剂量下，PHx 后 GSH 耗竭的程度相当，但丁硫氨酸亚砜胺给药抑制了肝重增加、血清丙氨酸氨基转移酶活性升高以及细胞周期蛋白 D1 和增殖细胞核抗原 (PCNA) 蛋白表达的肝再生进展，而磷苯处理的大鼠肝恢复明显加快，表明 GSH 在该过程中的作用最小。肝内蛋氨酸、S-腺苷甲硫氨酸、半胱氨酸、牛磺酸和 GSH 的浓度均因 PHx 而升高。残留肝中也诱导了蛋氨酸腺苷转移酶活性。丁硫氨酸亚砜胺给药抑制了 S-腺苷甲硫氨酸的升高，但增加了半胱氨酸向牛磺酸的分解代谢。相反，磷苯处理的大鼠中 S-腺苷甲硫氨酸升高，而半胱氨酸、次牛磺酸和牛磺酸降低。PHx 升高了肝腐胺和精脒，但降低了精胺浓度。丁硫氨酸亚砜胺给药进一步增加腐胺，但降低精脒和精胺浓度。相反，磷苯处理的大鼠中精脒和精胺浓度均升高。结果表明，S-腺苷甲硫氨酸的可用性通过增强多胺合成在肝再生的进展中起关键作用。这些发现提出了一种可能性，即调节肝转硫反应可能能够改变肝损伤后的恢复过程。
