Ethanol potentiates hypoxic liver injury: Role of hepatocyte Na+ overload

R. Carini, M. G. De Cesaris, R. Spendore, E. Albano

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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 HCO3--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. Copyright (C) 2000 Elsevier Science B.V.

Lingua originaleInglese
pagine (da-a)508-514
Numero di pagine7
RivistaBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1502
Numero di pubblicazione3
DOI
Stato di pubblicazionePubblicato - 15 nov 2000

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