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Glycine protects against hepatocyte killing by KCN or hypoxia by preventing intracellular Na+ overload in the rat

1997; Lippincott Williams & Wilkins; Volume: 26; Issue: 1 Linguagem: Inglês

10.1002/hep.510260114

1527-3350

Rita Carini, Giorgio Bellomo, M De Cesaris, Emanuele Albano,

Biochemical effects in animals

Glycine has been shown to prevent hepatocyte death induced by anoxia and by several toxic agents. However, the mechanisms responsible for such a cytoprotective effect have not yet been entirely clarified. We have previously shown that an uncontrolled increase in intracellular Na + is critical for hepatocyte killing induced by adenosine triphosphate (ATP) depletion. We herein report that protection by glycine (2 mmol/L) against cytotoxicity induced in isolated rat hepatocyte by potassium cyanide (KCN) or hypoxia was associated with the prevention of cytosolic Na + accumulation. The addition of the Na + ionophore, monensin, abolished the effects of glycine on both Na + increase and cytotoxicity. Pretreating hepatocytes with the glycine- receptor antagonist, strychnine (1 mmol/L), similarly prevented Na + overload and cell killing. Glycine at high concentrations and strychnine are known to block Cl − channels in many cell types. Consistently, we have observed that glycine and strychnine prevented the increase of intracellular Cl − levels caused by hypoxia or KCN. Incubation of hepatocytes in a Cl − -free medium, obtained by substituting chloride with membrane-impermeable gluconate, significantly reduced Na + accumulation and cell killing triggered by hypoxia or KCN. Both these effects were abolished by the addition of monensin. The cytoprotective action exerted by hepatocyte incubation in the Cl( − )-free medium was, however, lost when membrane-permeable nitrate, which allowed Na + accumulation, was used instead to replace chloride. Altogether, these results indicate that glycine inhibition of Cl − conductance protects against hepatocyte killing induced by KCN and hypoxia by interfering with intracellular Na + accumulation triggered by ATP depletion.