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 represent a valuable in vitro system for studying the metabolism and toxicity of xenobiotics. We have investigated their use for enzyme induction studies. Liver slices were prepared from male Sprague-Dawley rats and by using a dynamic culture system could be maintained in RPMI 1640 medium for up to 72 hr. The addition of 0.02-0.5 mm concentrations of ciprofibrate, nafenopin and Wy-14,643 for 48 and 72 hr produced a concentration and time dependent induction of palmitoyl-CoA oxidation and carnitine acetyltransferase activities. Ultrastructural examination of liver slices revealed an increase in the number of peroxisomes. Liver slices were also cultured with 0.2-5 mm phenobarbitone, 5-50 mum beta-naphthoflavone and 0.5-20 mug Aroclor 1254/ml and effects on the metabolism of 7-ethoxycoumarin, 7-benzoxyresorufin and 7-ethoxyresorufin determined. All three compounds produced a concentration and time dependent 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 respond to some known peroxisome proliferators and inducers of xenobiotic metabolism. Cultured liver slices may thus be a useful alternative in vitro system to hepatocytes for screening compounds for effects on various enzyme activities.
Lake
B G
BG
BIBRA Toxicology International, Woodmansterne Road, Carshalton, Surrey SM5 4DS, UK.
Beamand
J A
JA
Cunninghame
M E
ME
Davies
S
S
Mistry
H
H
Price
R J
RJ