ETHANOL-INDUCED FREE-RADICAL INJURY TO THE HEPATOCYTE GLUCAGON RECEPTOR

Plasma membrane receptors are essential in cellular homeostasis. Free radical generation and catalytic iron have been implicated in alcohol- induced liver injury; damage to plasma membrane receptors may be one i mportant mechanisms of injury. The effect of ethanol-induced free radi cals on hepatocyte receptor dysfunction was investigated in rodent mod els of free radical injury due to chronic alcohol administration. Rece ptors for glucagon and their postreceptor signal transduction pathway (cyclic AMP production [cAMP]) were investigated as sites of free radi cal injury in isolated perfused livers. Glucagon-stimulated cAMP decre ased (15%-80%) over a range of physiological (submaximal) doses of glu cagon after 6 weeks of ethanol feeding, while free radical generation (alkane evolution) increased greater than three to fourfold over basel ine (ethane; 2.04 +/- 0.36 vs. 0.58 +/- 0.08 pmole/10(6) cell/hr, p < 0.01; pentane 3.15 +/- 0.30 vs. 0.91 +/- 0.16, p < 0.01). Iron loading (125 mg/kg IP) potentiated this inhibition of cAMP production (40%-95 %) and further increased alkane production twofold (ethane 4.29 +/- 0. 78, pentane 5.76 +/- 0.71). Scatchard analysis revealed decreased numb ers of glucagon receptors paralleling cAMP responses. Free radical dam age to hepatocyte cell membrane receptors may be an important mechanis m of alcohol-induced liver injury.