X-Message-Number: 17136
Date: Sat, 28 Jul 2001 08:34:41 -0700 (PDT)
From: Doug Skrecky <>
Subject: sodium mediates ethanol toxicity

(but 4-methylpyrazole or cyanamide block this)

---------- Forwarded message ----------
Title
  Ethanol potentiates hypoxic liver injury: role of hepatocyte
  Na(+) overload.
Source
  Biochimica et Biophysica Acta.  1502(3):508-14, 2000 Nov 15.
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.

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