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Carini R, De Cesaris MG, Spendore R, Albano E: Ethanol potentiates hypoxic liver injury: role of hepatocyte Na (+) overload. Biochim Biophys Acta. 2000 Nov 15;1502(3):508-14.
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. |
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