Induction of cytochrome P450 isoenzymes in cultured precision-cut rat and human liver slices.
1. The effect of some xenobiotics on levels of selected cytochrome P450 (CYP) isoenzymes determined by Western immunoblotting and associated enzyme activities has been studied in 72-h cultured rat and human precision-cut liver slices. 2. In cultured rat liver slices, 0.5 mM sodium phenobarbitone (PB), 25 microM beta-naphthoflavone (BNF), and 20 micrograms/ml Aroclor 1254 (ARO) induced mixed-function oxidase enzyme activities. Western immunoblotting of liver slice microsomes was performed with antibodies to rat CYP1A2, 2B1/2 and 3A. Compared with 72-h control (dimethyl sulphoxide only treated) rat liver slice microsomes, PB induced CYP2B1/2 and 3A, BNF induced CYP1A2, and ARO induced CYP1A2, 2B1/2, and 3A. 3. The peroxisome proliferators methylclofenapate (MCP), ciprofibrate (CIP) and Wy-14,643 (WY) induced palmitoyl-CoA oxidation in 72-h cultured rat liver slices. Compared with 72-h control rat liver slice microsomes, MCP, CIP, and WY all induced levels of CYP4A. 4. In cultured human liver slices, 20 micrograms/ml ARO, but not 0.5 mM MCP, induced 7-ethoxyresorufin O-deethylase activity. Neither ARO nor MCP had any effect on homogenate palmitoyl-CoA oxidation and microsomal lauric acid 11- and 12-hydroxylase activities. Compared with 72-h control human liver slice microsomes, ARO induced CYP1A2, and MCP appeared to induce CYP4A. Further studies would be required to confirm that CYP4A isoenzymes could be induced by xenobiotics in human liver slices. 5. These results demonstrate that cultured liver slices may be used in evaluating the effect of xenobiotics on both rat and human CYP isoenzymes.
Lake
B G
BG
BIBRA International, Carshalton, UK.
Charzat
C
C
Tredger
J M
JM
Renwick
A B
AB
Beamand
J A
JA
Price
R J
RJ
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001571:Benzoflavones / Q000494:pharmacology; D020111:Chlorodiphenyl (54% Chlorine); D002992:Clofenapate / Q000494:pharmacology; D002995:Clofibric Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D046508:Culture Techniques; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D058607:Fibric Acids; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis*; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019324:beta-Naphthoflavone
D001140:Aroclors; D001571:Benzoflavones; D058607:Fibric Acids; D007527:Isoenzymes; D011743:Pyrimidines; D020111:Chlorodiphenyl (54% Chlorine); D002992:Clofenapate; D002995:Clofibric Acid; D019324:beta-Naphthoflavone; C006253:pirinixic acid; D003577:Cytochrome P-450 Enzyme System; C019304:ciprofibrate; D010634:Phenobarbital