Chen M K, Salloum R M, Austgen T R, Bland J B, Bland K I, Copeland E M, Souba W W
Department of Surgery, University of Florida College of Medicine, Gainesville.
JPEN J Parenter Enteral Nutr. 1991 Mar-Apr;15(2):159-64. doi: 10.1177/0148607191015002159.
Fast-growing tumors are major glutamine consumers and may alter host glutamine metabolism to benefit the tumor. Previous studies from our laboratory have demonstrated that the liver switches from an organ of glutamine balance to one of glutamine release with progressive malignant growth. However, the regulation of this change is unclear. This study examined tumor modulation of hepatic glutamine metabolism by determining the activities of glutaminase, the principle enzyme of glutamine degradation, and glutamine synthetase, the principal enzyme of glutamine synthesis. Hepatic glutamine content was also determined. Rats with a fast-growing subcutaneous fibrosarcoma (TBR) and pair-fed controls were studied at 2 and 3 weeks after tumor or sham implantation, when the tumors comprised approximately 5% and 20% of total body weight. Arterial glutamine fell with progressive tumor growth (608 +/- 26 mumol/L in controls vs 494 +/- 15 in TBR, p less than 0.005) and was not attributable to a diminished food intake. Hepatic glutamine content was increased 45% (p less than 0.01) in tumor rats at 2 weeks due in part to a 35% fall in liver glutaminase activity. At 3 weeks, glutamine synthetase activity increased by 43% (0.58 +/- 0.07 mumol/mg of protein/hr in controls vs 0.83 +/- 0.04 in TBR, p less than 0.01) whereas glutaminase remained depressed (2.68 +/- 0.12 mumol/mg of protein/hr in controls vs 2.22 +/- 0.15 in TBR, p less than 0.05) and glutamine content fell compared to 2 week tumor-bearing rats, consistent with accelerated hepatic glutamine release. Tumors may alter liver glutamine metabolism by modulating hepatic enzyme activity in order to provide circulating glutamine for the growing malignancy.
快速生长的肿瘤是谷氨酰胺的主要消耗者，可能会改变宿主的谷氨酰胺代谢以利于肿瘤生长。我们实验室之前的研究表明，随着恶性肿瘤的逐渐生长，肝脏从一个谷氨酰胺平衡的器官转变为一个释放谷氨酰胺的器官。然而，这种变化的调节机制尚不清楚。本研究通过测定谷氨酰胺降解的主要酶谷氨酰胺酶和谷氨酰胺合成的主要酶谷氨酰胺合成酶的活性，研究了肿瘤对肝脏谷氨酰胺代谢的调节作用。同时也测定了肝脏谷氨酰胺含量。对患有快速生长的皮下纤维肉瘤（TBR）的大鼠及其配对喂养的对照组在肿瘤植入或假手术植入后2周和3周进行研究，此时肿瘤分别约占体重的5%和20%。随着肿瘤的逐渐生长，动脉血谷氨酰胺水平下降（对照组为608±26μmol/L，TBR组为494±15μmol/L，p<0.005），且这并非由于食物摄入量减少所致。肿瘤大鼠在2周时肝脏谷氨酰胺含量增加了45%（p<0.01），部分原因是肝脏谷氨酰胺酶活性下降了35%。在3周时，谷氨酰胺合成酶活性增加了43%（对照组为0.58±0.07μmol/mg蛋白质/小时，TBR组为0.83±0.04μmol/mg蛋白质/小时，p<0.01），而谷氨酰胺酶仍处于抑制状态（对照组为2.68±0.12μmol/mg蛋白质/小时，TBR组为2.22±0.15μmol/mg蛋白质/小时，p<0.05），与2周荷瘤大鼠相比，谷氨酰胺含量下降，这与肝脏谷氨酰胺释放加速一致。肿瘤可能通过调节肝脏酶活性来改变肝脏谷氨酰胺代谢，以便为不断生长的恶性肿瘤提供循环谷氨酰胺。
