Functional hepatocyte heterogeneity in ammonia metabolism. The intercellular glutamine cycle.

In the rat liver acinus area synthesis and glutaminase activity are predominantly localized in the periportal area, whereas glutamine synthetase activity and the transport system for glutamate in the plasma membrane are perivenous. Detoxification of ammonium ions at low concentrations occurs exclusively by glutamine synthesis, but not by urea formation. Therefore, the two pathways of ammonia detoxification in the liver acinus represent the sequence of a low-affinity, but high-capacity system (urea synthesis) and a high-affinity system (glutamine synthesis). In agreement with this finding, obtained in experiments with the metabolically- and structurally-intact perfused rat liver, is also an almost complete inhibition of perivenous glutamine synthesis without impairment of periportal urea synthesis. This was shown after induction of a perivenous liver cell necrosis following CCl4 pretreatment with the consequence of a diminished hepatic ammonia extraction. Periportal glutaminase and perivenous glutamine synthetase are simultaneously active, resulting in an intercellular (as opposed to intracellular) glutamine cycle, being under the control of hormones, pH and portal ammonia and glutamine concentrations. The intercellular glutamine cycle provides an effective means for almost complete conversion of portal ammonium ions to urea by additional substrate supply of periportal urea synthesis, by periportal glutamine degradation and by the perivenous re-synthesis of glutamine from ammonia which escaped urea synthesis. Because urea synthesis, in contrast to glutamine synthesis, is a major pathway for the removal of bicarbonate, the switching of ammonia detoxification from urea synthesis to glutamine synthesis in acidosis or vice versa in alkalosis points to an important role of the liver in maintaining pH homeostasis. The acid-base-induced changes of the route of hepatic ammonia detoxification and therefore bicarbonate removal are performed by the regulatory properties of the enzymes of the intercellular glutamine cycle.