Induction of cytochrome P450 enzymes in cultured precision-cut human liver slices.
Article Details
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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
Drug Enzyme Kind Organism Pharmacological Action Actions Rifampicin Cytochrome P450 2A6 Protein Humans UnknownInducerDetails Rifampicin Cytochrome P450 2C19 Protein Humans UnknownInducerDetails Rifampicin Cytochrome P450 3A4 Protein Humans UnknownInducerDetails Rifamycin Cytochrome P450 2C19 Protein Humans NoInhibitorDetails Rifaximin Cytochrome P450 2C19 Protein Humans NoInducerDetails - Pharmaco-proteomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Rifampicin Approved CYP2C19 1557 increased Rifampin results in increased expression of CYP2C19 protein 10q23.33 Rifampicin Approved CYP3A4 1576 increased Rifampin results in increased expression of CYP3A4 protein 7q22.1 Rifampicin Approved CYP3A4 1576 increased Rifampin results in increased expression of CYP3A4 protein 7q22.1 Rifampicin Approved CYP3A4 1576 increased Rifampin results in increased expression of CYP3A4 protein 7q22.1 Phenobarbital Approved Investigational CYP3A4 1576 increased Phenobarbital results in increased expression of CYP3A4 protein 7q22.1 beta-Naphthoflavone Experimental CYP1A2 1544 increased beta-Naphthoflavone results in increased expression of CYP1A2 protein 15q24.1