CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications

Lin, Jiunn H.

doi:10.1007/s11095-006-0277-7

Cited by 242 publications

(189 citation statements)

References 217 publications

(250 reference statements)

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“…The drug-induced expression of the CYP3A4 gene in the liver, and to a lesser extent in the intestine, is predominantly regulated through PXR [15]. In contrast, VDR controls CYP3A4 transactivation by the secondary bile acid lithocholic acid (LCA) and subsequent biotransformation of LCA in the intestine [16,17].…”

Section: Introductionmentioning

confidence: 99%

Intestinal cell-specific vitamin D receptor (VDR)-mediated transcriptional regulation of CYP3A4 gene

Pávek

Pospěchová

Svecova

et al. 2010

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Abstract CYP3A4 is the most important drug-metabolizing enzyme that is involved in biotransformation of more than 50% of drugs. Pregnane X receptor (PXR) dominantly controls CYP3A4 inducibility in the liver, whereas vitamin D receptor (VDR) transactivates CYP3A4 in the intestine by secondary bile acids. Four major functional PXR-binding response elements of CYP3A4 have been discovered and their cooperation was found to be crucial for maximal up-regulation of the gene in hepatocytes. VDR and PXR recognize similar response element motifs and share DR3(XREM) and proximal ER6 (prER6) response elements of the CYP3A4 gene.In this work, we tested whether the recently discovered PXR response elements DR4(eNR3A4) in the XREM module and the distal ER6 element in the CLEM4 module We thus describe a specific ligand-induced VDR-mediated transactivation of the CYP3A4 gene in intestinal cells that differs PXR-mediated CYP3A4 regulation in hepatocytes.

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Section: Introductionmentioning

confidence: 99%

Intestinal cell-specific vitamin D receptor (VDR)-mediated transcriptional regulation of CYP3A4 gene

Pávek

Pospěchová

Svecova

et al. 2010

Biochemical Pharmacology

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“…It catalyzes the metabolism of more than 50% of clinically used drugs (Schuetz, 2004). Induction of CYP3A4 can result in clinically significant drug-drug interactions or autoinduction (Lin, 2006) and, therefore, is a major concern for the pharmaceutical industry.…”

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confidence: 99%

Comparison of Immortalized Fa2N-4 Cells and Human Hepatocytes as in Vitro Models for Cytochrome P450 Induction

Hariparsad¹,

Carr²,

Evers³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Fa2N-4 cells have been proposed as a tool to identify CYP3A4 inducers. To evaluate whether Fa2N-4 cells are a reliable surrogate for cryopreserved human hepatocytes, we assessed the basal mRNA expression of 64 drug disposition genes in Fa2N-4 cells. Significant differences were found in the expression of major drugmetabolizing enzymes, nuclear receptors, and transporters between both cell types. Importantly, the expression of constitutive androstane receptor (CAR) and several hepatic uptake transporters was significantly lower (>50-fold) in Fa2N-4 cells, whereas the expression of pregnane X-receptor (PXR) and aryl hydrocarbon receptor (

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“…Several studies have reported induction by DMSO of several P450s, especially the CYP3A subfamily, in both primary hepatocytes (LeCluyse et al, 2000;Su and Waxman, 2004;Lin, 2006) and hepatoma cell lines (Aninat et al, 2006). Although most effects were obtained with a 2% DMSO concentration, some increase was also seen with concentrations as low as 0.1% in primary human hepatocytes (LeCluyse et al, 2000).…”

Section: Downloaded Frommentioning

confidence: 99%

Liverbeads: A Practical and Relevant In Vitro Model for Gene Induction Investigations

Khansa¹,

Blanck²,

Bars³

2010

Drug Metab Dispos

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ABSTRACT:Cryopreserved rat hepatocytes entrapped within an alginate matrix, commercially available as Liverbeads, were evaluated for their relevance as a screening tool for gene induction in vitro, using quantitative real-time reverse transcriptase-polymerase chain reaction. They were treated with the reference compounds ␤-naphthoflavone (BNF), phenobarbital (PB), pregnenolone 16␣-carbonitrile (PCN), and clofibric acid (CLO) and analyzed for mRNA levels of Cyp1a1, Cyp2b1, Cyp3a1, Cyp4a1, Ugt1a6, and Ugt2b1. In addition, for PB and PCN, the results were compared with those obtained in rat liver in vivo. For each inducer, the gene induction profiles obtained with the Liverbeads in vitro model were time-and dose-dependent. The in vitro gene expression profiles confirmed the corresponding known P450 and UGT induction by each reference compound.

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CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications

Cited by 242 publications

References 217 publications

Intestinal cell-specific vitamin D receptor (VDR)-mediated transcriptional regulation of CYP3A4 gene

Intestinal cell-specific vitamin D receptor (VDR)-mediated transcriptional regulation of CYP3A4 gene

Comparison of Immortalized Fa2N-4 Cells and Human Hepatocytes as in Vitro Models for Cytochrome P450 Induction

Liverbeads: A Practical and Relevant In Vitro Model for Gene Induction Investigations

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