TY - JOUR
T1 - Ethanol potentiates hypoxic liver injury
T2 - Role of hepatocyte Na+ overload
AU - Carini, R.
AU - De Cesaris, M. G.
AU - Spendore, R.
AU - Albano, E.
N1 - Funding Information:
This work has been supported by the Ministry of University and Scientific and Technologic Research, Rome (Project: Patologia da Radicali Liberi e degli Equilibri Redox).
PY - 2000/11/15
Y1 - 2000/11/15
N2 - 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.
AB - 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.
KW - Acidosis
KW - Alcohol related liver injury
KW - Cell death
KW - Hypoxia
KW - Sodium
UR - http://www.scopus.com/inward/record.url?scp=0034670101&partnerID=8YFLogxK
U2 - 10.1016/S0925-4439(00)00075-2
DO - 10.1016/S0925-4439(00)00075-2
M3 - Article
SN - 0925-4439
VL - 1502
SP - 508
EP - 514
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 3
ER -