CHANGES IN CYTOCHROME-P-450, CYTOCHROME-P-450-2E1, CYTOCHROME-P-450-2B1, AND CYTOCHROME-P-450-4A, AND PHOSPHOLIPASE-A AND PHOSPHOLIPASE-C IN THE INTRAGASTRIC FEEDING RAT MODEL FOR ALCOHOLIC LIVER-DISEASE - RELATIONSHIP TO DIETARY FATS AND PATHOLOGICAL LIVER-INJURY

The influence of dietary fat and alcohol on hepatic microsomal levels of cytochromes P-450 2E1, 2B, and 4A; phospholipases A and C; and UDP- glucuronosyltransferase was studied in the intragastric feeding rat mo del for alcoholic liver injury. Eight groups of animals were evaluated . Control and ethanol fed rats received either saturated fat or corn o il and were killed after 2 weeks and 1 month of feeding. All animals w ere pair-fed by continuous infusion of liquid diet through permanently implanted gastric cannulas. Alcoholic liver injury developed only in the corn oil-ethanol fed groups and was manifest by 1 month. Livers we re subjected to the following analyses: pathologic evaluation of liver injury; levels of cytochromes P-450 2E1, 2B, and 4A protein and mRNA; aniline hydroxylase activity; and phospholipase A and C and UDP-glucu ronosyltransferase activities. Ethanol induced increases in cytochrome s P-450 2E1 and 2B protein determined by Western blotting were greates t in the corn oil-ethanolfed group, which developed pathologic changes in the liver. Cytochromes P-450 2E1 and 2B1 mRNA levels were unaffect ed, suggesting that posttranscriptional mechanisms are responsible for the increase in the corresponding P-450 proteins. In contrast, cytoch rome P-450 4A levels were higher in the saturated fat-ethanol groups c ompared with the corn oil-ethanol groups. Phospholipase A and phosphol ipase C levels were higher in the corn oil-ethanol groups compared wit h pair-fed dextrose controls and the saturated fat-ethanol groups. UDP -glucuronosyltransferase levels declined with time in the ethanol-fed groups. These observations are discussed in the context of a model whe reby the induction of phospholipases A and C and cytochromes P-450 2E1 and 2B1 in corn oil-ethanol-fed rats provide arachidonic acid substra te and induce lipid peroxidation, respectively. These changes may acco unt for the more severe pathologic changes that develop in corn oil-et hanol-fed animals compared with animals fed saturated fat and ethanol.