GADOLINIUM CHLORIDE BLOCKS ALCOHOL-DEPENDENT LIVER TOXICITY IN RATS TREATED CHRONICALLY WITH INTRAGASTRIC ALCOHOL DESPITE THE INDUCTION OF CYP2E1

Hepatic CYP2E1 is induced in several models of alcohol administration, but clinically relevant pathology is only observed in rats in a model involving the continuous intragastric administration of an ethanol-co ntaining, corn oil-based, high-fat diet. The level of CYP2E1 correlate s with the degree of liver pathology in the intragastric feeding model , which leads to the hypothesis that radical production by CYP2E1 is r esponsible for the pathology. Destruction of the Kupffer cells with ga dolinium chloride (GdCl3) prevented the development of ethanol-depende nt pathology and decreased the production of radicals that appeared in the bile of intragastrically alcohol-fed rats. If the induction of CY P2E1 and subsequent formation of oxidant species by the enzyme is caus ative in the ethanol-dependent hepatic pathology, then protection by G dCl3 could be due an inhibition of CYP2E1 induction. In the current st udy, ethanol-administration for 4 wk produced marked steatosis, necros is, and inflammation not seen in control rats. Immunochemically, CYP2E 1 was induced 5- to 6-fold in microsomes from the ethanol-treated anim als. Rates of p-nitrophenol and chlorzoxazone hydroxylation were eleva ted approximately 3-fold, consistent with CYP2E1 induction. When GdCl3 was administered with ethanol, there was a decrease of approximately 80% in Kupffer cell receptor expression, and there was a significant d ecrease in hepatic pathology, which confirms previous studies. However , in the ethanol and GdCl3-treated animals, there was no significant d ecrease in the induction of CYP2E1. CYP2E1 was elevated approximately 5-fold, as estimated by immunoblot analysis, and rates of p-nitropheno l and chlorzoxazone hydroxylation were elevated 3- to 4-fold in ethano l + GdCl3-treated rats. Thus, these results clearly dissociate the ind uction of CYP2E1 by intragastric infusion of ethanol from the generati on of early alcohol-induced liver disease. It is concluded that Kupffe r cells rather than CYP2E1 play the major role in the initiation of he patocyte damage caused by alcohol.