Häussinger D
Adv Enzyme Regul. 1986;25:159-80. doi: 10.1016/0065-2571(86)90013-0.
In the liver acinus, urea synthesis and glutaminase activity are predominantly localized in the periportal area, whereas glutamine synthetase activity is perivenous. Because ammonium ions at low concentrations are effectively removed by glutamine synthetase, but not by urea synthesis, the two pathways of ammonia detoxication in the liver acinus represent the sequence of a low-affinity, but high-capacity system (ureogenesis) and a perivenous high-affinity system (glutamine synthesis). In agreement with these findings, obtained in experiments with the metabolically and structurally intact perfused rat liver, perivenous glutamine synthesis was almost completely inhibited after induction of perivenous liver cell necrosis by carbon tetrachloride, whereas periportal urea synthesis was not affected. The structural and functional organization of hepatic ammonium and glutamine metabolism and the metabolic interactions of different subacinar hepatocyte populations provide a new understanding of hepatic nitrogen metabolism under physiological and pathological conditions. Periportal glutaminase and perivenous glutamine synthetase are simultaneously active, resulting in an intercellular (as opposed to intracellular) glutamine cycle, being under complex metabolic and hormonal control. The intercellular glutamine cycle provides an effective means for almost complete conversion of portal ammonium ions into urea without accompanying net glutamine formation. This is achieved by additional substrate feeding into the urea cycle by the glutaminase reaction, both pathways being localized in the periportal compartment, and the perivenous resynthesis of glutamine from ammonium ions which escaped periportal urea synthesis. This complete conversion of portal ammonium ions into urea by means of glutamine cycling represents the situation of a well-balanced pH homeostasis. Because urea synthesis, in contrast to glutamine synthesis, is a major pathway for removal of bicarbonate, the switching of hepatic ammonium detoxication from urea synthesis to glutamine synthesis in acidosis points to an important role of the liver in maintaining pH homeostasis. The acid-base-induced changes of the route of hepatic ammonium detoxication and therefore bicarbonate removal are performed by the regulatory properties of the enzymes of the intercellular glutamine cycle.
在肝腺泡中，尿素合成和谷氨酰胺酶活性主要定位于门周区域，而谷氨酰胺合成酶活性则位于中央静脉周围。由于低浓度的铵离子可被谷氨酰胺合成酶有效清除，但不能通过尿素合成清除，因此肝腺泡中氨解毒的两条途径代表了一个低亲和力但高容量系统（尿素生成）和一个中央静脉周围高亲和力系统（谷氨酰胺合成）的顺序。与在代谢和结构完整的灌注大鼠肝脏实验中获得的这些发现一致，四氯化碳诱导中央静脉周围肝细胞坏死后，中央静脉周围的谷氨酰胺合成几乎完全受到抑制，而门周尿素合成不受影响。肝脏铵和谷氨酰胺代谢的结构和功能组织以及不同亚腺泡肝细胞群体的代谢相互作用为生理和病理条件下的肝脏氮代谢提供了新的认识。门周谷氨酰胺酶和中央静脉周围谷氨酰胺合成酶同时活跃，导致细胞间（而非细胞内）谷氨酰胺循环，该循环受复杂的代谢和激素控制。细胞间谷氨酰胺循环为将门静脉铵离子几乎完全转化为尿素提供了一种有效手段，而不会伴随净谷氨酰胺形成。这是通过谷氨酰胺酶反应将额外的底物输入尿素循环来实现的，这两条途径都位于门周区室，以及从逃脱门周尿素合成的铵离子重新合成中央静脉周围的谷氨酰胺。通过谷氨酰胺循环将门静脉铵离子完全转化为尿素代表了pH稳态良好平衡的情况。由于与谷氨酰胺合成不同，尿素合成是清除碳酸氢盐的主要途径，酸中毒时肝脏氨解毒从尿素合成转向谷氨酰胺合成表明肝脏在维持pH稳态中起重要作用。酸碱诱导的肝脏氨解毒途径以及因此碳酸氢盐清除的变化是由细胞间谷氨酰胺循环中酶的调节特性完成的。
