INDUCTION OF CYTOCHROME-P450 ISOENZYMES IN CULTURED PRECISION-CUT RATAND HUMAN LIVER SLICES

1. The effect of some xenobiotics on levels of selected cytochrome P45 0 (CYP) isoenzymes determined by Western immunoblotting and associated enzyme activities has been studied in 72-h cultured rat and human pre cision-cut liver slices. 2. In cultured rat liver slices, 0.5 mM sodiu m phenobarbitone (PB), 25 mu M beta-naphthoflavone (BNF), and 20 mu g/ 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 (di methyl sulphoxide only treated) rat liver slice microsomes, PB induced CYP2B1/2 and 3A, BNF induced CYP1A2, and ARO induced CYP1A2, 2B1/2, a nd 3A. 3. The peroxisome proliferators methylclofenapate (MCP), ciprof ibrate (CIP) and Wy-14,643 (WY) induced palmitoyl-CoA oxidation in 72- h cultured rat liver slices. Compared with 72-h control rat liver slic e microsomes, MCP, CIP, and WY all induced levels of CYP4A. 4. In cult ured human liver slices, 20 mu g/ml ARO, but not 0.5 mM MCP, induced 7 -ethoxyresorufin O-deethylase activity. Neither ARO nor MCP had any ef fect on homogenate palmitoyl-CoA oxidation and microsomal lauric acid 11- and 12-hydroxylase activities. Compared with 72-h control human li ver slice microsomes, ARO induced CYP1A2, and MCP appeared to induce C YP4A. Further studies would be required to confirm that CYP4A isoenzym es could be induced by xenobiotics in human liver slices. 5. These res ults demonstrate that cultured liver slices may be used in evaluating the effect of xenobiotics on both rat and human CYP isoenzymes.