RT Journal Article
SR Electronic
T1 Induction of Cytochrome P450 Enzymes in Cultured Precision-Cut Human Liver Slices
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 282
OP 288
DO 10.1124/dmd.31.3.282
VO 31
IS 3
A1 Robert J. Edwards
A1 Roger J. Price
A1 Patricia S. Watts
A1 Anthony B. Renwick
A1 J. Michael Tredger
A1 Alan R. Boobis
A1 Brian G. Lake
YR 2003
UL http://dmd.aspetjournals.org/content/31/3/282.abstract
AB Precision-cut human liver slices obtained from 11 donors were cultured for 72 h in a defined medium (serum free Williams' medium E) supplemented with 0.1 μM insulin and 0.1 μM dexamethasone (DEX). Liver slices were treated with 50 μM concentrations of β -naphthoflavone (BNF), lansoprazole, rifampicin (RIF), DEX and methylclofenapate and 500 μM sodium phenobarbital (NaPB). The relative apoprotein levels of 12 cytochrome P450 (P450) enzymes were determined in liver slice microsomes using a panel of antipeptide antibodies. Treatment with BNF significantly induced mean levels of CYP1A2 apoprotein to 160% of levels in 72-h control (no test compound) human liver slice microsomes. NaPB significantly induced levels of CYP3A4 apoprotein to 255% of control and RIF significantly induced levels of CYP2C19 and CYP3A4 apoproteins to 265 and 330% of control, respectively. In addition, treatment with RIF increased levels of CYP2A6 apoprotein to 205% of control, and treatment with both NaPB and RIF increased levels of CYP2B6 apoprotein to 370 and 615% of control, respectively. However, these increases were not statistically significant, owing to a variable response between liver slice preparations from different subjects, this being apparent for all inducible P450s. In contrast, none of the compounds examined significantly increased levels of CYP2C8, CYP2C9, CYP2D6, CYP2E1, and CYP4A11 apoproteins. Levels of CYP1A1 apoprotein were not detected in any liver slice sample, either before or after treatment with the model inducers. Overall, these results demonstrate the utility of cultured human liver slices for assessing the effects of chemicals on P450 enzymes. The American Society for Pharmacology and Experimental Therapeutics