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.