Waverunner
Senior Member
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Rifaximin seems to work as an Pregnane-X-Receptor agonist. This receptor is expressed all over the gut and is implicated in inflammatory bowel diseases. The mechanisms behind are not fully understood but Rifaximin seems to have a lot more beneficial effects, besides being an antibiotic. It seems to increase gut integrity, which also can be explained through the Pregnane-X-Receptor, it seems to prevent insulin resistance and it seems to have anti-inflammatory effects that should be taken into consideration.
http://www.ncbi.nlm.nih.gov/pubmed/20816942
J Pharmacol Exp Ther. 2007 Jul;322(1):391-8. Epub 2007 Apr 18.
Rifaximin is a gut-specific human pregnane X receptor activator.
Source
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bldg. 37, Room 3106, Bethesda, MD 20892, USA.
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bldg. 37, Room 3106, Bethesda, MD 20892, USA.
Abstract
Rifaximin, a rifamycin analog approved for the treatment of travelers' diarrhea, is also beneficial in the treatment of multiple chronic gastrointestinal disorders. However, the mechanisms contributing to the effects of rifaximin on chronic gastrointestinal disorders are not fully understood. In the current study, rifaximin was investigated for its role in activation of the pregnane X receptor (PXR), a nuclear receptor that regulates genes involved in xenobiotic and limited endobiotic deposition and detoxication. PXR-humanized (hPXR), Pxr-null, and wild-type mice were treated orally with rifaximin, and rifampicin, a well characterized human PXR ligand. Rifaximin was highly concentrated in the intestinal tract compared with rifampicin. Rifaximin treatment resulted in significant induction of PXR target genes in the intestine of hPXR mice, but not in wild-type and Pxr-null mice. However, rifaximin treatment demonstrated no significant effect on hepatic PXR target genes in wild-type, Pxr-null, and hPXR mice. Consistent with the in vivo data, cell-based reporter gene assay revealed rifaximin-mediated activation of human PXR, but not the other xenobiotic nuclear receptors constitutive androstane receptor, peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma, and farnesoid X receptor. Pretreatment with rifaximin did not affect the pharmacokinetics of the CYP3A substrate midazolam, but it increased the C(max) and decreased T(max) of 1'-hydroxymidazolam. Collectively, the current study identified rifaximin as a gut-specific human PXR ligand, and it provided further evidence for the utility of hPXR mice as a critical tool for the study of human PXR activators. Further human studies are suggested to assess the potential role of rifaximin-mediated gut PXR activation in therapeutics of chronic gastrointestinal disorders.
Rifaximin, a rifamycin analog approved for the treatment of travelers' diarrhea, is also beneficial in the treatment of multiple chronic gastrointestinal disorders. However, the mechanisms contributing to the effects of rifaximin on chronic gastrointestinal disorders are not fully understood. In the current study, rifaximin was investigated for its role in activation of the pregnane X receptor (PXR), a nuclear receptor that regulates genes involved in xenobiotic and limited endobiotic deposition and detoxication. PXR-humanized (hPXR), Pxr-null, and wild-type mice were treated orally with rifaximin, and rifampicin, a well characterized human PXR ligand. Rifaximin was highly concentrated in the intestinal tract compared with rifampicin. Rifaximin treatment resulted in significant induction of PXR target genes in the intestine of hPXR mice, but not in wild-type and Pxr-null mice. However, rifaximin treatment demonstrated no significant effect on hepatic PXR target genes in wild-type, Pxr-null, and hPXR mice. Consistent with the in vivo data, cell-based reporter gene assay revealed rifaximin-mediated activation of human PXR, but not the other xenobiotic nuclear receptors constitutive androstane receptor, peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma, and farnesoid X receptor. Pretreatment with rifaximin did not affect the pharmacokinetics of the CYP3A substrate midazolam, but it increased the C(max) and decreased T(max) of 1'-hydroxymidazolam. Collectively, the current study identified rifaximin as a gut-specific human PXR ligand, and it provided further evidence for the utility of hPXR mice as a critical tool for the study of human PXR activators. Further human studies are suggested to assess the potential role of rifaximin-mediated gut PXR activation in therapeutics of chronic gastrointestinal disorders.
PMID:
17442842
[PubMed - indexed for MEDLINE]
17442842
[PubMed - indexed for MEDLINE]
Trends Pharmacol Sci.
2012 Jun;33(6):323-30. Epub 2012 May 18.
Pregnane X receptor as a target for treatment of inflammatory bowel disorders.
Source
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract
Pregnane X receptor (PXR; NR1I2), a member of the nuclear receptor superfamily, has a major role in the induction of genes involved in drug transport and metabolism. Recent studies in mice have provided insight into a novel function for PXR in inflammatory bowel disease (IBD). The mechanism of the protective effect of PXR activation on IBD is not fully established, but is due in part to the attenuation of nuclear factor (NF)-κB signaling that results in lower expression of proinflammatory cytokines. Recent clinical trials with the antibiotic rifaximin, a PXR agonist in the gastrointestinal system, have revealed its potential therapeutic value in the treatment of intestinal inflammation in humans. Thus, PXR may be a novel target for IBD therapy.
Published by Elsevier Ltd.
Pregnane X receptor (PXR; NR1I2), a member of the nuclear receptor superfamily, has a major role in the induction of genes involved in drug transport and metabolism. Recent studies in mice have provided insight into a novel function for PXR in inflammatory bowel disease (IBD). The mechanism of the protective effect of PXR activation on IBD is not fully established, but is due in part to the attenuation of nuclear factor (NF)-κB signaling that results in lower expression of proinflammatory cytokines. Recent clinical trials with the antibiotic rifaximin, a PXR agonist in the gastrointestinal system, have revealed its potential therapeutic value in the treatment of intestinal inflammation in humans. Thus, PXR may be a novel target for IBD therapy.
Published by Elsevier Ltd.
http://www.ncbi.nlm.nih.gov/pubmed/20816942
Biochem Pharmacol. 2010 Dec 1;80(11):1700-7. Epub 2010 Sep 9.
Pregnane-X-receptor mediates the anti-inflammatory activities of rifaximin on detoxification pathways in intestinal epithelial cells.
Source
Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Facoltà di Medicina e Chirurgia, Via Gerardo Dottori, no. 1 S. Andrea delle Fratte, 06132 Perugia, Italy.
Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Facoltà di Medicina e Chirurgia, Via Gerardo Dottori, no. 1 S. Andrea delle Fratte, 06132 Perugia, Italy.
Abstract
The pregnane-X-receptor (PXR) is master gene overseeing detoxification of wide number of xenobiotics and is critical for maintenance of intestinal integrity. The intestinal expression of genes involved in cellular detoxification is down-regulated in patients with inflammatory bowel diseases (IBD). Rifaximin is a non-absorbable antibiotic endowed with a PXR agonistic activity. In the present study we have investigated whether rifaximin activates PXR in primary human colon epithelial cells and human colon biopsies and assessed whether this antibiotic antagonizes the effect of tumor necrosis factor (TNF)-α on expression of PXR and PXR-related genes. Present results demonstrate that primary colon epithelial cells express PXR and that their exposure to rifaximin induces the expression of genes involved in cellular detoxification. Exposure to TNFα reduces the expression of PXR mRNA as well as expression of its target genes. This inhibitory effect was prevented by that co-treatment with rifaximin. Knocking down the expression of PXR in colon epithelial cells by an anti-PXR siRNA, abrogated the counter-regulatory effects exerted by rifaximin on cell exposed to TNFα. Finally, ex vivo exposure of colon biopsies obtained from ulcerative colitis patients to rifaximin increased the expression of genes involved in xenobiotics metabolism. In aggregate, these data illustrate that rifaximin increases the expression of PXR and PXR-regulated genes involved in the metabolism and excretion of xenobiotics and antagonizes the effects of TNFα in intestinal epithelial cells and colon biopsies. These non-antibiotic effects of rifaximin could contribute to the maintenance of the intestinal barrier integrity against xenobiotics and products generated by luminal bacteria.
Copyright © 2010 Elsevier Inc. All rights reserved.
http://www.ncbi.nlm.nih.gov/pubmed/22723881
PLoS One. 2012;7(6):e38734. Epub 2012 Jun 18.
Activation of Pregnane X Receptor by Pregnenolone 16 α-carbonitrile Prevents High-Fat Diet-Induced Obesity in AKR/J Mice.
Ma Y, Liu D.
Source
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, United States of America.
Abstract
Pregnane X receptor (PXR) is known to function as a xenobiotic sensor to regulate xenobiotic metabolism through selective transcription of genes responsible for maintaining physiological homeostasis...These results verify the important function of PXR in lipid and energy metabolism and suggest that PXR represents a novel therapeutic target for prevention and treatment of obesity and insulin resistance.
The pregnane-X-receptor (PXR) is master gene overseeing detoxification of wide number of xenobiotics and is critical for maintenance of intestinal integrity. The intestinal expression of genes involved in cellular detoxification is down-regulated in patients with inflammatory bowel diseases (IBD). Rifaximin is a non-absorbable antibiotic endowed with a PXR agonistic activity. In the present study we have investigated whether rifaximin activates PXR in primary human colon epithelial cells and human colon biopsies and assessed whether this antibiotic antagonizes the effect of tumor necrosis factor (TNF)-α on expression of PXR and PXR-related genes. Present results demonstrate that primary colon epithelial cells express PXR and that their exposure to rifaximin induces the expression of genes involved in cellular detoxification. Exposure to TNFα reduces the expression of PXR mRNA as well as expression of its target genes. This inhibitory effect was prevented by that co-treatment with rifaximin. Knocking down the expression of PXR in colon epithelial cells by an anti-PXR siRNA, abrogated the counter-regulatory effects exerted by rifaximin on cell exposed to TNFα. Finally, ex vivo exposure of colon biopsies obtained from ulcerative colitis patients to rifaximin increased the expression of genes involved in xenobiotics metabolism. In aggregate, these data illustrate that rifaximin increases the expression of PXR and PXR-regulated genes involved in the metabolism and excretion of xenobiotics and antagonizes the effects of TNFα in intestinal epithelial cells and colon biopsies. These non-antibiotic effects of rifaximin could contribute to the maintenance of the intestinal barrier integrity against xenobiotics and products generated by luminal bacteria.
Copyright © 2010 Elsevier Inc. All rights reserved.
http://www.ncbi.nlm.nih.gov/pubmed/22723881
PLoS One. 2012;7(6):e38734. Epub 2012 Jun 18.
Activation of Pregnane X Receptor by Pregnenolone 16 α-carbonitrile Prevents High-Fat Diet-Induced Obesity in AKR/J Mice.
Ma Y, Liu D.
Source
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, United States of America.
Abstract
Pregnane X receptor (PXR) is known to function as a xenobiotic sensor to regulate xenobiotic metabolism through selective transcription of genes responsible for maintaining physiological homeostasis...These results verify the important function of PXR in lipid and energy metabolism and suggest that PXR represents a novel therapeutic target for prevention and treatment of obesity and insulin resistance.
