EFFECTS OF SHORT-TERM ETHANOL AND NUTRITION ON THE HEPATIC-MICROSOMAL MONOOXYGENASE SYSTEM IN A MODEL UTILIZING TOTAL ENTERAL NUTRITION IN THE RAT

The majority of studies examining the effects of ethanol on the hepatic microsomal monooxygenase system, (HMO), have utilized the liquid diet regimen of Lieber and DeCarli. While much has been learned with this useful model, there are some concerns associated with diminished nutrient intake. Decreased food intake in the presence of high levels of ethanol could give rise to at least three effects; primary ethanol effects, primary nutritional effects and/or effects resulting from interactions between nutritional deficiencies and ethanol (i.e., synergistic effects). A model similar to that developed by Tsukomoto and French is used in the current study, in which ethanol is infused directly into the stomach as part of a total enteral nutrition system (TEN). This assured that nutrients sufficient for normal growth were consumed. Two clinically relevant diets were selected for study. One diet is very similar to that used for intravenous feeding of human patients (diet A) and the other similar to that used for intragastric feeding of patients (diet B). The present study was conducted to determine the effects of different diets on HMO and to determine whether ethanol has demonstrable effects in the presence of dietary sources that promote normal growth rates. The effects of the two liquid diets alone or of TEN where 35% of the total calories in the diets were replaced by ethanol for 8 days were examined on HMO of adult male Sprague-Dawley rats. HMO substrates examined included testosterone, the alkoxyresorufins, carbon tetrachloride, and p-nitrophenol. Levels of cytochrome P-450 apoproteins were studied by Western blot analysis. The content of monooxygenase components and of some P-450 isozymes including CYP 2E1 were nutritionally dependent. Short-term ethanol treatment caused a 2- to 4-fold induction in CYP 2E1 (rat P-450j) apoprotein in TEN systems utilizing the two different diets. This difference in inducibility was reflected in differential increases in CYP 2E1 dependent p-nitrophenol hydroxylation and carbon tetrachloride-dependent lipid peroxidation. In addition, dietary-dependent changes were seen in testosterone but not alkoxyresorufin metabolism after short-term ethanol treatment. In particular, dietary-dependent ethanol effects were observed on testosterone 6-beta-hydroxylase activity and associated apoproteins of the P-450 gene family 3 in Western blot analysis using a polyclonal antibody directed against CYP 3A2. The results of these studies suggest: (1) that short-term dietary ethanol can induce CYP 2E1 in well nourished animals but that the level of induction is smaller than that previously reported using Lieber-DeCarli pair-feeding regimens; (2) that diet alone has a significant influence on constitutive levels of P-450 isozymes including CYP 2E1; (3) that diet influences the effects of ethanol on HMO; and (4) that the TEN system is a useful model for the study of diet/drug interactions.