EFFECT OF PEROXISOME PROLIFERATORS AND INDUCERS OF XENOBIOTIC METABOLISM ON MARKER ENZYME-ACTIVITIES IN CULTURED RAT-LIVER SLICES

Previous work has demonstrated that precision-cut liver slices represe nt a valuable in vitro system for studying the metabolism and toxicity of xenobiotics. We have investigated their use for enzyme induction s tudies. Liver slices were prepared from male Sprague-Dawley rats and b y using a dynamic culture system could be maintained in RPMI 1640 medi um for up to 72 hr. The addition of 0.02-0.5 mM concentrations of cipr ofibrate, nafenopin and Wy-14,643 for 48 and 72 hr produced a concentr ation and time dependent induction of palmitoyl-CoA oxidation and carn itine acetyltransferase activities. Ultrastructural examination of liv er slices revealed an increase in the number of peroxisomes. Liver sli ces were also cultured with 0.2-5 mM phenobarbitone, 5-50 mu M beta-na phthoflavone and 0.5-20 mu g Aroclor 1254/ml and effects on the metabo lism of 7-ethoxycoumarin, 7-benzoxyresorufin and 7-ethoxyresorufin det ermined. All three compounds produced a concentration and time depende nt induction of mixed-function oxidase enzyme activities. The results of this study demonstrate that rat liver slices can be cultured for up to 72 hr and appear to retain functional viability in that they respo nd to some known peroxisome proliferators and inducers of xenobiotic m etabolism. Cultured liver slices may thus be a useful alternative in v itro system to hepatocytes for screening compounds for effects on vari ous enzyme activities.