BUMETANIDE-SENSITIVE CELL SWELLING MEDIATES THE INHIBITORY EFFECT OF ETHANOL ON PROTEOLYSIS IN RAT-LIVER

Background & Aims: Ethanol is known to inhibit proteolysis and to caus e intracellular protein accumulation in the liver. The aim of this stu dy was to investigate the mechanism underlying the antiproteolytic eff ect of ethanol. Methods: The effects of ethanol on proteolysis and cel l volume were assessed in the isolated perfused rat liver by establish ed tracer techniques. Results: Infusion of ethanol (20 mmol/L) led to an increase of the intracellular water space by 9.3% +/- 0.4% (n = 3), which was abolished by methylpyrazole and mimicked by acetaldehyde (5 mmol/L). Ethanol-induced cell swelling was completely abolished by bu metanide (5 mu mol/ L), an inhibitor of Na-K-2Cl cotransport. Ethanol (20 mmol/L) inhibited proteolysis by 18.6% +/- 2.0% (n = 4) in a colch icine-sensitive way. This antiproteolytic effect was quantitatively mi micked by equipotent hyposmotic hepatocyte swelling and by acetaldehyd e. Ethanol-induced inhibition of proteolysis was abolished in the pres ence of methylpyrazole (100 mu mol/L), bumetanide (5 mu mol/L), furose mide (100 mu mol/L), and insulin (35 nmol/L), i.e., conditions that al so prevented ethanol-induced cell swelling. Conclusions: Ethanol cause s, via acetaldehyde, bumetanide-sensitive cell swelling, which in turn mediates the antiproteolytic effect of this alcohol. The data indicat e the involvement of cell hydration changes in mediating metabolic eth anol effects and could suggest the activation of a putative Na-K-2Cl c otransport in liver by ethanol/acetaldehyde.