AMMONIA AND GLUTAMINE-METABOLISM IN HUMAN-LIVER SLICES - NEW ASPECTS ON THE PATHOGENESIS OF HYPERAMMONEMIA IN CHRONIC LIVER-DISEASE
AMMONIA AND GLUTAMINE-METABOLISM IN HUMAN-LIVER SLICES - NEW ASPECTS ON THE PATHOGENESIS OF HYPERAMMONEMIA IN CHRONIC LIVER-DISEASE
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DOI：
10.1111/j.1365-2362.1988.tb01053.x
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发表时间：
1988-10-01
影响因子：
5.5
通讯作者：
HAUSSINGER, D
中科院分区：
文献类型：
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作者：
KAISER, S;GEROK, W;HAUSSINGER, D
在正常、脂肪和肝硬化人类肝脏切片中研究了氨和谷氨酰胺代谢。通过组织学检查评估肝脏疾病。相对于氨的去除，尿素和谷氨酰胺的合成在人肝脏中代表低和高亲和力系统与K0.5（NH 4+）值分别为3.6和0.11 mM。与正常对照肝相比，缺氧肝表现出从NH_4Cl合成谷氨酰胺减少约80%。尿素合成也是如此。 相反，通过肝转氨酶的流量在肝硬化中增加4-6倍。无论是否参考肝脏湿重、DNA或蛋白质含量，均观察到肝脏谷氨酰胺和氨代谢的这些变化。乙酰唑胺抑制尿素合成在肝硬化肝切片约50%，表明线粒体碳酸酐酶是尿素合成所需的肝硬化。体外测定的NH 4Cl尿素合成能力与体内测定的血浆碳酸氢盐浓度之间存在显著相关性。这些数据表明：（i）慢性肝病中高氨血症的发病机制涉及能够合成谷氨酰胺的静脉周围氨清除细胞的损伤;（ii）在肝硬化中观察到的通过谷氨酰胺酶的通量增加增加，增加了进入尿素循环的氨输入，并作为维持生命相容的尿素循环通量的代偿机制，尽管尿素循环酶活性降低;（iii）碳酸酐酶为氨甲酰磷酸合成酶提供的线粒体内碳酸氢盐在肝硬化中也可能成为速率控制;（iv）慢性肝病中的高碳酸氢盐血症可能是由于尿素合成导致的肝脏HCO 3清除受损所致，这与肝脏在全身酸碱平衡中的作用的概念一致。
Ammonia and glutamine metabolism was studied in slices from normal, fatty and cirrhotic human livers. The liver disease was evaluated by histological examination. WIth respect to ammonia removal, urea and glutamine synthesis in human liver represent low and high affinity systems with K0.5(NH4+) values of 3.6 and 0.11 mM, respectively. Compared with normal control livers, cirrhotic livers showed a decreased glutamine sythesis from NH4Cl by about 80%. The same was ture for urea synthesis. Conversely, flux through hepatic glutaminase was increased in cirrhosis 4-6-fold. These changes in hepatic glutamine and ammonia metabolism were observed regardless of whether reference was made to liver wet weight, DNA or protein content. Acetazolamide inhibited urea synthesis in cirrhotic liver slices by about 50%, indicating that mitochondrial carbonic anhydrase is required for urea synthesis also in cirrhosis. There was a significant correlation between the in-vitro determined capacity for urea synthesis from NH4Cl and the in-vivo determined plasma bicarbonate concentration. The data suggest that (i) pathogenesis of hyperammonaemia in chronic liver disease involves the impairment of the perivenous ammonia scavenger cells capable of glutamine synthesis; (ii) the increased flux through glutaminase observed in cirrhosis increases the ammonia input into the urea cycle and acts as a compensatory mechanism for maintenance of a life-compatible urea cycle flux despite the decreased urea cycle enzyme activities; (iii) intramitochondrial bicarbonate provision for carbamoylphosphate synthetase by carbonic anhydrase may become rate-controlling also in liver cirrhosis; and (iv) hyperbicarbonataemia in chronic liver disease may, amongst other effects, be due to an impaired hepatic HCO3- removal by urea synthesis, in line with the concept of a role of the liver in systemic acid-base homeostasis.