Rifamycin SV exhibits strong anti-inflammatory in vitro activity through pregnane X receptor stimulation and NFκB inhibition.

Abstract

Rifamycin SV (rifamycin), is a member of the ansamycin family of antimicrobial compounds which kills bacteria commonly associated with infectious diarrhea and other enteric infections. Rifamycin has been found to be effective in experimental animal models of gut inflammation and its efficacy in these settings has been attributed partially to immunomodulatory non-bactericidal activities. This study aimed to further evaluate the anti-inflammatory activities of rifamycin by analyzing its effect on two key regulators of inflammation: PXR and NFκB. Rifamycin stimulated PXR transcriptional activity in two PXR reporter cell lines and induced expression of two genes known to be regulated by PXR and are directly involved in cellular detoxification: CYP3A4 and PgP. Moreover, CYP3A4 metabolic activity was induced by rifamycin in HepG2 cells. Rifamycin also antagonized TNFα and LPS-induced NFκB activities and inhibited IL1β-induced synthesis of inflammatory chemokine, IL8. Although reciprocal regulation of PXR and NFkB by rifamycin was not directly addressed, the data suggest that in the absence of PXR, inhibition of NFκB by rifamycin is not dependent on PXR stimulation. Thus, rifamycin exhibits potent anti-inflammatory activities, characterized by in vitro PXR activation and concomitant CYP3A4 and PgP induction, in parallel with potent NFκB inhibition and concomitant IL8 inhibition.

• Authors: Caridad Rosette, Frances J Agan, Niccolette Rosette, Luigi Moro, Alessandro Mazzetti, Cesare Hassan, Mara Gerloni
• Journal: Drug metabolism and pharmacokinetics (Drug Metab Pharmacokinet) Vol. 34 Issue 3 Pg. 172-180 (Jun 2019) ISSN: 1880-0920 [Electronic] England
• PMID: 31101589 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Anti-Inflammatory Agents
• NF-kappa B
• NR1I2 protein, human
• Pregnane X Receptor
• Rifamycins
• rifamycin SV
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics)
• Anti-Inflammatory Agents (pharmacology)
• Caco-2 Cells
• Cell Culture Techniques
• Cytochrome P-450 CYP3A (genetics)
• HT29 Cells
• Hep G2 Cells
• Humans
• NF-kappa B (antagonists & inhibitors, genetics)
• Pregnane X Receptor (genetics)
• Rifamycins (pharmacology)
• Signal Transduction
• Transcriptional Activation (drug effects)