Induction of cytochrome P450 enzymes in cultured precision-cut human liver slices.

Article Details

Citation

Edwards RJ, Price RJ, Watts PS, Renwick AB, Tredger JM, Boobis AR, Lake BG

Induction of cytochrome P450 enzymes in cultured precision-cut human liver slices.

Drug Metab Dispos. 2003 Mar;31(3):282-8.

PubMed ID
12584154 [ View in PubMed
]
Abstract

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 microM insulin and 0.1 microM dexamethasone (DEX). Liver slices were treated with 50 microM concentrations of beta -naphthoflavone (BNF), lansoprazole, rifampicin (RIF), DEX and methylclofenapate and 500 microM 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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
RifampicinCytochrome P450 2A6ProteinHumans
Unknown
Inducer
Details
RifampicinCytochrome P450 2C19ProteinHumans
Unknown
Inducer
Details
RifampicinCytochrome P450 3A4ProteinHumans
Unknown
Inducer
Details
RifamycinCytochrome P450 2C19ProteinHumans
No
Inhibitor
Details
RifaximinCytochrome P450 2C19ProteinHumans
No
Inducer
Details
Pharmaco-proteomics
DrugDrug GroupsGeneGene IDChangeInteractionChromosome
RifampicinApprovedCYP2C191557
increased
Rifampin results in increased expression of CYP2C19 protein10q23.33
RifampicinApprovedCYP3A41576
increased
Rifampin results in increased expression of CYP3A4 protein7q22.1
RifampicinApprovedCYP3A41576
increased
Rifampin results in increased expression of CYP3A4 protein7q22.1
RifampicinApprovedCYP3A41576
increased
Rifampin results in increased expression of CYP3A4 protein7q22.1
PhenobarbitalApproved InvestigationalCYP3A41576
increased
Phenobarbital results in increased expression of CYP3A4 protein7q22.1
beta-NaphthoflavoneExperimentalCYP1A21544
increased
beta-Naphthoflavone results in increased expression of CYP1A2 protein15q24.1