Effects of rifampicin on global gene expression in human small intestine

Oscarson, Mikael; Burk, Oliver; Winter, Stefan; Schwab, Matthias; Wolbold, Renzo; Dippon, Juergen; Eichelbaum, Michel; Meyer, Urs

doi:10.1097/fpc.0b013e3280143dfc

Cited by 24 publications

(23 citation statements)

References 66 publications

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“…We assumed that a stimulus inducing the transcription of ABCC2 could be accompanied by altered expression of miRNAs controlling ABCC2 gene expression on the post-transcriptional level. We therefore treated HepG2 cells, which provide readily detectable ABCC2 expression under normal growth conditions, with the PXR ligand and inducer of ABCC2 transcription rifampicin (Gerk and Vore, 2002;Kast et al, 2002;Oscarson et al, 2007). As proof of concept, we could detect a significant up-regulation of ABCB1 protein (Martin et al, 2008).…”

Section: Discussionmentioning

confidence: 81%

Down-Regulation of ATP-Binding Cassette C2 Protein Expression in HepG2 Cells after Rifampicin Treatment Is Mediated by MicroRNA-379

Haenisch¹,

Laechelt²,

Bruckmueller³

et al. 2011

Mol Pharmacol

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microRNAs (miRNAs), which contribute to the post-transcriptional processing through 3Ј-untranslated region-interference, have been shown to be involved in the regulation of ATPbinding cassette (ABC) membrane transporters. The aim of this study was to investigate whether ABCC2, an important efflux transporter for various endogenous and exogenous compounds at several compartment barriers, is subject to miRNAmediated post-transcriptional gene regulation. We screened the expression of 377 human miRNAs in HepG2 cells after 48 h of treatment with 5 M rifampicin [a pregnane X receptor (PXR) ligand] or vehicle using reverse transcription-polymerase chain reaction-based low-density arrays. Specific miRNA, ABCC2 mRNA, and protein expression were monitored in HepG2 cells undergoing rifampicin treatment for 72 h. Loss-and gain-offunction experiments and reporter gene assays were performed for further confirmation. Highly deregulated miRNAs compared with in silico data revealed miRNA (miR) 379 as candidate miRNA targeting ABCC2 mRNA. Under rifampicin treatment, ABCC2 mRNA increased significantly, with a maximal fold change of 1.56 Ϯ 0.43 after 24 h. In addition, miR-379 increased (maximally 4.10 Ϯ 1.33-fold after 48 h), whereas ABCC2 protein decreased with a maximal fold change of 0.47 Ϯ 0.08 after 72 h. In contrast, transfection of miR-379 inhibitor led to an elevation of ABCC2 protein expression after rifampicin incubation for 48 h. We identify a miRNA negatively regulating ABCC2 on the post-transcriptional level and provide evidence that this miRNA impedes overexpression of ABCC2 protein after a PXR-mediated external transcriptional stimulus in HepG2 cells.

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Section: Discussionmentioning

confidence: 81%

Down-Regulation of ATP-Binding Cassette C2 Protein Expression in HepG2 Cells after Rifampicin Treatment Is Mediated by MicroRNA-379

Haenisch¹,

Laechelt²,

Bruckmueller³

et al. 2011

Mol Pharmacol

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“…Treatment with the PXR ligand rifampicin in healthy humans significantly increases the mRNA and protein level of CYP2C9, 2C8 and 2C19 as well as their enzymatic activity in the small intestine [63-65]. The order of inducibility is similar to that in hepatic CYP2C s: 2C8 > 2C9 > 2C19 [64], but the induction response is reported to be weaker (about 1.5-fold at the mRNA level) in the small intestine than in the liver, as quantified using intestinal biopsies [65]. Notably, CAR, PXR, and HNF4α are also expressed in the small intestine.…”

Section: Transcriptional Regulation Of Cyp2c Genes In Extrahepatic Timentioning

confidence: 99%

The Transcriptional Regulation of the Human CYP2C Genes

Chen¹,

Goldstein²

2009

CDM

111

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In humans, four members of the CYP2C subfamily (CYP2C8, CYP2C9, CYP2C18, and CYP2C19) metabolize more than 20% of all therapeutic drugs as well as a number of endogenous compounds. The CYP2C enzymes are found predominantly in the liver, where they comprise ∼20% of the total cytochrome P450. A variety of xenobiotics such as phenobarbital, rifampicin, and hyperforin have been shown to induce the transcriptional expression of CYP2C genes in primary human hepatocytes and to increase the metabolism of CYP2C substrates in vivo in man. This induction can result in drug-drug interactions, drug tolerance, and therapeutic failure. Several drug-activated nuclear receptors including CAR, PXR, VDR, and GR recognize drug responsive elements within the 5′ flanking promoter region of CYP2C genes to mediate the transcriptional upregulation of these genes in response to xenobiotics and steroids. Other nuclear receptors and transcriptional factors including HNF4α, HNF3γ, C/EBPα and more recently RORs, have been reported to regulate the constitutive expression of CYP2C genes in liver. The maximum transcriptional induction of CYP2C genes appears to be achieved through a coordinative cross-talk between drug responsive nuclear receptors, hepatic factors, and coactivators. The transcriptional regulatory mechanisms of the expression of CYP2C genes in extrahepatic tissues has received less study, but these may be altered by perturbations from pathological conditions such as ischemia as well as some of the receptors mentioned above.

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“…PXR-mediated regulation of human hepatic and intestinal MRP2 is suggested by rifampin-dependent induction in the HepG2 hepatoma cell line [101,106], in cultured primary human hepatocytes [85,86,99,107], and in duodenal biopsies of rifampintreated volunteers in vivo [19,92,93]. Another PXR ligand, hyperforin, was also shown to induce MRP2 mRNA in primary human hepatocyte cultures [99].…”

Section: Induction In Liver and Intestinementioning

confidence: 98%

“…Treatment with numerous microsomal enzyme inducers, e.g., rifampin, clotrimazole, RU486, carbamazepine, nifedipine, artemisinin, all now known to activate PXR, induces the expression of MDR1 in human intestinal LS180 and LS174T cells [54,[88][89]. Using this experimental approach, it was shown that rifampin [90][91][92][93], SJW [75], and carbamazepine [98] induce the expression of MDR1/P-gp in human small intestine. In vivo induction of intestinal MDR1 was demonstrated by comparing the expression in small intestinal biopsies before and after treatment of volunteers with the inducer.…”

Section: Induction In Liver and Intestinementioning

confidence: 99%