AJP - Cell Physiology, Vol 262, Issue 5 C1175-C1180, Copyright © 1992 by American Physiological Society
Ethanol metabolism and inhibition of nucleoside uptake lead to increased extracellular adenosine in hepatocytes
L. E. Nagy
Department of Nutritional Sciences, University of Guelph, Ontario, Canada.
Recent evidence suggests that adenosine mediates many of the acute and
chronic effects of ethanol in both cultured cells and whole animals. These
adenosine-mediated effects of ethanol result from ethanol-induced increases
in extracellular adenosine. Acute exposure of primary cultures of rat
hepatocytes to 12.5-200 mM ethanol increased extracellular adenosine
concentrations by 20-35%. Pretreatment of hepatocytes with 100 microM
4-methylpyrazole, an inhibitor of alcohol dehydrogenase, completely blocked
ethanol-induced increases in extracellular adenosine at 12.5 and 25 mM
ethanol. However, even in the presence of 4-methylpyrazole, ethanol at
concentrations greater than 50 mM still increased extracellular adenosine
concentrations. This increase appears to be due to ethanol inhibition of
adenosine uptake via the nucleoside transporter (50% inhibitory
concentration, 28 mM). After chronic treatment with 100 mM ethanol for 48
h, acute challenge with ethanol no longer inhibited adenosine uptake, i.e.,
the nucleoside transporter had become tolerant to ethanol. Moreover, in
these chronically treated cells, ethanol-induced increases in extracellular
adenosine were completely blocked by treatment with 4-methylpyrazole at all
concentrations of ethanol. Taken together, these results suggest that
increased extracellular adenosine in hepatocytes is dependent on both
ethanol oxidation and inhibition of adenosine uptake via the nucleoside
transporter.
