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 important mechanisms of injury. The effect of ethanol-induced free radicals on hepatocyte receptor dysfunction was investigated in rodent models of free radical injury due to chronic alcohol administration. Receptors for glucagon and their postreceptor signal transduction pathway (cyclic AMP production [cAMP]) were investigated as sites of free radical injury in isolated perfused livers. Glucagon-stimulated cAMP decreased (15%-80%) over a range of physiological (submaximal) doses of glucagon after 6 weeks of ethanol feeding, while free radical generation (alkane evolution) increased greater than three to fourfold over baseline (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 numbers of glucagon receptors paralleling cAMP responses. Free radical damage to hepatocyte cell membrane receptors may be an important mechanism of alcohol-induced liver injury.
Shaw
S
S
Department of Medicine, V.A. Medical Center, Bronx, NY 10468, USA.
Eng
J
J
Jayatilleke
E
E
D000473:Alkanes / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D005609:Free Radicals; D005934:Glucagon / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000187:drug effects* / Q000502:physiology
D000473:Alkanes; D005609:Free Radicals; D018027:Receptors, Glucagon; D000431:Ethanol; D005934:Glucagon; D000242:Cyclic AMP