Neurochemical Research

, Volume 39, Issue 3, pp 593-598

First online:

Glutamine in the Pathogenesis of Hepatic Encephalopathy: The Trojan Horse Hypothesis Revisited

  • Kakulavarapu V. Rama RaoAffiliated withDepartment of Pathology, University of Miami Miller School of Medicine
  • , Michael D. NorenbergAffiliated withDepartment of Pathology, University of Miami Miller School of MedicineBiochemistry and Molecular Biology, University of Miami Miller School of MedicineVeterans Affairs Medical Center Email author 

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Hepatic encephalopathy (HE) is major neuropsychiatric disorder occurring in patients with severe liver disease and ammonia is generally considered to represent the major toxin responsible for this condition. Ammonia in brain is chiefly metabolized (“detoxified”) to glutamine in astrocytes due to predominant localization of glutamine synthetase in these cells. While glutamine has long been considered innocuous, a deleterious role more recently has been attributed to this amino acid. This article reviews the mechanisms by which glutamine contributes to the pathogenesis of HE, how glutamine is transported into mitochondria and subsequently hydrolyzed leading to high levels of ammonia, the latter triggering oxidative and nitrative stress, the mitochondrial permeability transition and mitochondrial injury, a sequence of events we have collectively termed as the Trojan horse hypothesis of hepatic encephalopathy.


Ammonia Astrocytes Glutamine Glutaminase Hepatic encephalopathy l-Histidine 6-Diazo-5-oxo-l-norleucine (DON) Mitochondrial permeability transition Oxidative stress