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Department of Physiology and Pharmacology, Oregon Health Sciences
University, Portland, Oregon 97201 (D.R.K., B.K.), and
Department of
Pharmacology, University of North Carolina, Chapel Hill, North Carolina
27599 (Y.I., R.G.T.)
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-containing, corn oil-based, high-fat diet. The level of CYP2E1
correlates with the degree of liver pathology in the intragastric
feeding model, which leads to the hypothesis that radical production by
CYP2E1 is responsible for the pathology. Destruction of the Kupffer
cells with gadolinium chloride (GdCl3) prevented the
development of ethanol-dependent pathology and decreased the production
of radicals that appeared in the bile of intragastrically alcohol-fed
rats. If the induction of CYP2E1 and subsequent formation of oxidant
species by the enzyme is causative in the ethanol-dependent hepatic
pathology, then protection by GdCl3 could be due an
inhibition of CYP2E1 induction. In the current study,
ethanol-administration for 4 wk produced marked steatosis, necrosis,
and inflammation not seen in control rats. Immunochemically, CYP2E1 was
induced 5- to 6-fold in microsomes from the ethanol-treated animals.
Rates of p-nitrophenol and chlorzoxazone hydroxylation
were elevated 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 decrease in hepatic pathology, which confirms
previous studies. However, in the ethanol and GdCl3-treated
animals, there was no significant decrease in the induction of CYP2E1.
CYP2E1 was elevated approximately 5-fold, as estimated by immunoblot
analysis, and rates of p-nitrophenol and chlorzoxazone
hydroxylation were elevated 3- to 4-fold in ethanol + GdCl3-treated rats. Thus, these results clearly dissociate
the induction of CYP2E1 by intragastric infusion of ethanol from the
generation of early alcohol-induced liver disease. It is concluded that
Kupffer cells rather than CYP2E1 play the major role in the initiation
of hepatocyte damage caused by alcohol.
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