Ethanol potentiates hypoxic liver injury: role of hepatocyte Na(+) overload.

Abstract

Centrilobular hypoxia has been suggested to contribute to hepatic damage caused by alcohol intoxication. However, the mechanisms involved are still poorly understood. We have investigated whether alterations of Na(+) homeostasis might account for ethanol-mediated increase in hepatocyte sensitivity to hypoxia. Addition of ethanol (100 mmol/l) to isolated rat hepatocytes incubated under nitrogen atmosphere greatly stimulated cell death. An increase in intracellular Na(+) levels preceded cell killing and Na(+) levels in hepatocytes exposed to the combination of ethanol and hypoxia were almost twice those in hypoxic cells without ethanol. Na(+) increase was also observed in hepatocytes incubated with ethanol in oxygenated buffer. Ethanol addition significantly lowered hepatocyte pH. Inhibiting ethanol and acetaldehyde oxidation with, respectively, 4-methylpyrazole and cyanamide prevented this effect. 4-methylpyrazole, cyanamide as well as hepatocyte incubation in a HCO(3)(-)-free buffer or in the presence of Na(+)/H(+) exchanger blocker 5-(N,N-dimethyl)-amiloride also reduced Na(+) influx in ethanol-treated hepatocytes. 4-methylpyrazole and cyanamide similarly prevented ethanol-stimulated Na(+) accumulation and hepatocyte killing during hypoxia. Moreover, ethanol-induced Na(+) influx caused cytotoxicity in hepatocytes pre-treated with Na(+), K(+)-ATPase inhibitor ouabain. Also in this condition 4-methylpyrazole and 5-(N,N-dimethyl)-amiloride decreased cell killing. These results indicate that ethanol can promotes cytotoxicity in hypoxic hepatocytes by enhancing Na(+) accumulation.

• Authors: R Carini, M G De Cesaris, R Spendore, E Albano
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1502 Issue 3 Pg. 508-14 (Nov 15 2000) ISSN: 0006-3002 [Print] Netherlands
• PMID: 11068192 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Pyrazoles
• Ethanol
• Cyanamide
• Fomepizole
• Adenosine Triphosphate
• Sodium

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Cell Hypoxia
• Cell Separation
• Cell Survival (drug effects)
• Cells, Cultured
• Cyanamide (pharmacology)
• Ethanol (antagonists & inhibitors, toxicity)
• Fomepizole
• Hydrogen-Ion Concentration
• In Vitro Techniques
• Ischemia (metabolism, pathology)
• Liver (drug effects, metabolism, pathology)
• Liver Diseases (metabolism, pathology)
• Male
• Perfusion
• Pyrazoles (pharmacology)
• Rats
• Rats, Wistar
• Sodium (analysis, metabolism)