DIFFERENTIAL-EFFECTS OF MONENSIN ON ASIALOGLYCOPROTEIN RECEPTOR FUNCTION AFTER SHORT-TERM ETHANOL ADMINISTRATION

Chronic ethanol consumption is associated with multiple impairments in receptor-mediated endocytosis (RME) by the hepatic asialoglycoprotein receptor (ASGP-R). Previous work on this receptor has shown that its activity can be perturbed by the carboxylic ionophore monensin. This a gent has been shown to preferentially affect receptor-ligand dissociat ion and receptor redistribution of one subset (State 2) of ASGP-R, whi le receptor function in a second subset (State 1 receptors) is unaffec ted. In the present study, we examined the effect of monensin on ASGP- R activity and intracellular receptor-ligand dissociation after 7-10 d ays of ethanol feeding, a time when we have shown altered ASGP-R funct ion in ethanol-fed animals. Hepatocytes from male Wistar rats tied an ethanol containing or control diet) were utilised. Ethanol administrat ion decreased total ligand binding by 35-40% (P < 0.01) without a chan ge in receptor protein content. After monensin treatment, surface rece ptors on cells from control animals were inactivated and redistributed to the cell interior. In cells from ethanol-fed animals, a similar pa ttern of monensin-induced inactivation was shown, but no redistributio n occurred. Intracellular receptor-ligand dissociation was impaired in both cell types, although the monensin-induced effect on dissociation was significantly less dramatic (two-fold) in the hepatocytes from et hanol-fed animals as compared with controls. Thus, although receptors on both cell types were susceptible to monensin, cells from the ethano l-fed animals were less vulnerable to the added effects of this agent. Since monensin affects functioning of State 2, but not State 1 recept ors, a very early effect of ethanol may be a preferential impairment i n the State 2 receptor population. (C) 1998 Elsevier Science Inc.