Role of p38 map kinase in glycine-induced hepatocyte resistance to hypoxic injury

J Hepatol. 2007 Apr;46(4):692-9. doi: 10.1016/j.jhep.2006.10.014. Epub 2006 Nov 27.


Background/aims: Glycine hepatoprotection is well known. However, the mechanisms involved are still poorly characterized.

Methods: Glycine protection was investigated in isolated rat hepatocytes pretreated with 2 mmol/L glycine 15 min before incubation under hypoxic conditions.

Results: Glycine significantly reduced Na+ overload and hepatocyte death caused by hypoxia. Glycine protection required the activation of a signal pathway involving Src, Pyk2 and p38 MAP kinases. Glycine treatment also induced a 11% increase of hepatocyte volume and transient ATP release. The prevention of cell swelling by hepatocyte incubation in a hypertonic medium as well as the degradation of extracellular ATP with apyrase or the block P2 purinergic receptors with suramin reverted glycine-induced cytoprotection and inhibited Src, Pyk2 and p38 MAPK activation. Glycine down-modulated Na+/H+ exchanger (NHE) activity, without affecting the development of intracellular acidosis during hypoxia. Such an effect was reverted by inhibiting p38 MAPK that also abolished glycine protection against Na+ overload caused by hypoxia.

Conclusions: Glycine-induced ATP release in response to a moderate hepatocyte swelling led to the autocrine stimulation of P2 receptors and to the activation of Src, Pyk2 and p38 MAPK that increased hepatocyte resistance to hypoxia by preventing Na+ influx through NHE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Autocrine Communication
  • Cell Hypoxia / physiology*
  • Cytoprotection*
  • Enzyme Activation
  • Focal Adhesion Kinase 2 / metabolism
  • Glycine / pharmacology*
  • Hepatocytes / drug effects*
  • Hepatocytes / enzymology*
  • Hepatocytes / metabolism
  • Homeostasis / drug effects
  • Male
  • Rats
  • Rats, Wistar
  • Receptors, Purinergic P2 / metabolism
  • Signal Transduction
  • Sodium / metabolism
  • Sodium-Hydrogen Exchangers / metabolism
  • Water / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism*
  • src-Family Kinases / metabolism


  • Receptors, Purinergic P2
  • Sodium-Hydrogen Exchangers
  • Water
  • Adenosine Triphosphate
  • Sodium
  • Focal Adhesion Kinase 2
  • src-Family Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Glycine