The Effect of Rifampin Treatment on Intestinal Expression of Human MRP Transporters

Fromm, Martin F.; Kauffmann, Hans-Martin; Fritz, Péter; Burk, Oliver; Kroemer, Heyo K.; Warzok, R; Eichelbaum, Michel; Siegmund, Werner; Schrenk, Dieter

doi:10.1016/s0002-9440(10)64794-3

Cited by 266 publications

(155 citation statements)

References 41 publications

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“…Thus, there appear to be species differences in the ability of PXR ligands to induce P-gp in humans and rats. Rifampin treatment induced another member of the ATP-binding cassette transporter family, MRP2 at both the mRNA and protein levels in intact human intestine (Fromm et al, 2000b). This result was extended to primary cultures of human hepatocytes, in which PXR ligands, rifampicin and HIV protease inhibitors, caused a significant increase in MRP2 mRNA level ).…”

Section: Induction Of Multiple Drug Resistance Genes In Ratsmentioning

confidence: 76%

Tissue Distribution and Chemical Induction of Multiple Drug Resistance Genes in Rats

Cherrington²,

et al. 2002

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ABSTRACT:Multiple drug resistance (mdr) genes encode P-glycoprotein, which is responsible for resistance to some cancer chemotherapeutic drugs and efflux of xenobiotics of cells. Thus, mdr can protect organs from xenobiotics. In rats, there are two mdr1 genes capable of xenobiotic transport, mdr1a and mdr1b. The purpose of this study was to determine the tissue distribution of rat mdr1a and mdr1b mRNA and whether microsomal enzyme inducers that increase phase I and II drug-metabolizing enzymes coordinately regulate mdr1a and/or mdr1b. The mRNA levels of mdr1a and mdr1b were determined using branched-DNA signal amplification technology. The highest level of expression of mdr1a mRNA was observed in the gastrointestinal tract, with levels increasing, respectively, from duodenum, jejunum, and ileum to large intestine. Expression levels of mdr1a mRNA in the cerebral cortex, cerebellum, kidney, lung, and liver were less than one-tenth of that in the ileum. The tissue distribution of mdr1b mRNA was similar to mdr1a with highest expression in the gastrointestinal tract but only about 3-fold higher than in most other tissues. The induction of mdr1a and mdr1b mRNA transcripts in liver, kidney, and ileum by treatment of rats with 18 chemicals representing aryl hydrocarbon receptor ligands, constitutive androstane receptor ligands, pregnane X receptor ligands, peroxisome proliferator-activated receptor ligands, electrophile-response-element activators, and CYP4502E1 inducers was assessed. Hepatic, renal, and intestinal expression of mdr1a and mdr1b mRNA were not significantly altered by treatment of rats with any of these classes of ligands. In conclusion, the primary expression of rat mdr1 genes is in the gastrointestinal tract where they are thought to function to decrease the absorption of some xenobiotics. Rat mdr1 gene expression is not readily increased by microsomal enzyme inducers in rats through coordinate mechanisms with phase I and II drugmetabolizing enzymes.

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Section: Induction Of Multiple Drug Resistance Genes In Ratsmentioning

confidence: 76%

Tissue Distribution and Chemical Induction of Multiple Drug Resistance Genes in Rats

Cherrington²,

et al. 2002

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“…It has been found that this sequence also interacts with PXR and the constitutive androstane receptor. Indeed, most of the PXR ligands such as rifampicin and hyperforin have been shown to upregulate MRP2 expression in humans, mice, and rats (Fromm et al 2000, Kast et al 2002, Anapolsky et al 2006. Excess glucocorticoid concentrations increase the MRP2 mRNA levels, which implicates glucocorticoidinducible PXR activation (Kliewer et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells

Choi¹,

Yang²,

Roh³

et al. 2007

Endocr Relat Cancer

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Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem in breast cancer patients. The transition from chemotherapy-responsive breast cancer cells to chemotherapy-resistant cancer cells is mainly accompanied by the increased expression of multidrug resistanceassociated proteins (MRPs). In this study, it was found that TAM-resistant MCF-7 (TAMR-MCF-7) cells expressed higher levels of MRP2 than control MCF-7 cells. Molecular analyses using MRP2 gene promoters supported the involvement of the pregnane X receptor (PXR) in MRP2 overexpression in TAMR-MCF-7 cells. Although CCAAT/enhancer-binding protein b was overexpressed continuously in TAMR-MCF-7 cells, this might not be responsible for the transcriptional activation of the MRP2 gene. In addition, the basal activities of phosphatidylinositol 3-kinase (PI3-kinase) were higher in the TAMR-MCF-7 cells than in the control cells. The inhibition of PI3-kinase significantly reduced both the PXR activity and MRP2 expression in TAMR-MCF-7 cells. Overall, MRP2 induction plays a role in the additional acquisition of chemotherapy resistance in TAM-resistant breast cancer.

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“…The growing list of PXR target genes include, in addition to CYP3A family members, CYP2B6 (Wang et al 2003), Cyp7a1 (cholesterol 7 a-hydroxylase; Staudinger et al 2001), UDP-glucuronosyltransferase 1A1 (Hartley et al 2004), intestinal P-glycoprotein (Geick, Eichelbaum, and Burk 2001), OATP2 (Hartley et al 2004), and MRP2 (Fromm et al 2000).…”

Section: Pxr Phenotypementioning

confidence: 99%

Liver Hypertrophy

Elcombe²,

et al. 2012

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Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPARa. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach.

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The Effect of Rifampin Treatment on Intestinal Expression of Human MRP Transporters

Cited by 266 publications

References 41 publications

Tissue Distribution and Chemical Induction of Multiple Drug Resistance Genes in Rats

Tissue Distribution and Chemical Induction of Multiple Drug Resistance Genes in Rats

Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells

Liver Hypertrophy

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