药物代谢组学案例分析

药理研究：奥曲肽的肝脏保护作用

研究对象：大鼠

分析检测平台：GC-TOF／MS（BIOTREE）

期刊：Liver international

影响因子：4.85

发表时间：2015

摘要：

Background & Aims: Insufficient liver regeneration and hepatocyte injury caused by excessive portal perfusion are considered to be responsible for post-hepatectomy liver failure (PLF) or small-for-size syndrome in living- donor liver transplantation. Somatostatin can decrease portal vein pressure (PVP) but simultaneously inhibits liver regeneration. This interesting para- dox motivated us to investigate the outcome of PLF in response to somatostatin treatment. Methods: Rats receiving extended partial hepatectomy (90% PH) were treated with octreotide, a somatostatin analogue, or placebo. Animal survival, serum parameters and hepatic histology were evaluated. Metabolomic analysis was performed to investigate the effect of octreotide on hepatocyte metabolism. Results: Despite significantly inhibiting early regeneration, octreotide application noticeably improved the hepatic histology, liver function and survival after PH but did not decrease the PVP level. Metabolomic analysis exhibited that octreotide profoundly and exclusively altered the levels of five metabolites that participate in or closely associate with the methionine cycle, a biochemical reaction that uniquely produces S-adenosylmethionine (SAMe), an active methyl residual donor for methyl- transferase reactions. Among these metabolites, methylthioadenosine (MTA), a derivate of SAMe, increased three-fold and was found independently improve the hepatic histology and reduce inflammatory cytokines in hepatectomized rats. Conclusions: Octreotide exclusively regulates the methionine cycle reaction and augments the MTA level in hepatocytes. MTA prominently protects hepatocytes against shear stress injury and reduces the secondary inflammation, thereby protecting rats from PLF.

Keywords: hepatectomy liver failure (PLF)、portal vein pressure (PVP)、methylthioadenosine (MTA)

研究背景：

肝脏在部分切除后仍可通过激活成熟肝细胞进行自我修复，这一特点是肝脏切除术及肝脏活体移植（living-donor liver transplantation， LDLT）技术的重要基础。然而在治疗复杂肝脏疾病时，采用肝脏切除术后常发现术后肝功能失常（post-hepatectomy liver failure, PLF），且肝脏移植后常出现小体积综合症（small-for-size syndrome, SFSS），导致术后死亡率升高。

门静脉过度灌注是PLF的重要征兆，同时门静脉血压和剪切力升高也可直接导致SFSS。因此降低门静脉血压可作为预防SFSS和PLF的一种有效策略。奥曲肽是一种生长抑素，具有降低PVP作用，临床常用于治疗肝硬化引起的上消化道出血。虽然有报道称奥曲肽可降低SFSS发生率，但其机制尚不明确。同时，作为生长抑素，该药品是否会因抑制肝脏细胞再生而导致PLF尚不确定。为尝试回答这些问题，本文尝试在大鼠肝切除术模型中研究奥曲肽的作用效果和机制。

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