The grapefruit flavonoid naringenin as a Hepatitis C virus therapy : efficacy, mechanism and delivery

[摘要] (cont.) This work begins by characterizing the link between VLDL secretion and HCV production in the Huh7.5.1/JFH-1 system. We proceed to examine the effects of naringenin, a grapefruit flavonoid, on the production of HCV. Naringenin has been shown previously to reduce VLDL secretion from hepatocytes, and we demonstrate its ability to block HCV production, as well. We explore the mechanism of naringenin;;s effect on HCV, and show that the flavonoid prevents the assembly of infectious viruses in the cell. Despite previous success by several groups in describing the mechanisms involved in naringenin;;s effect on VLDL secretion, these mechanisms are thought to account only for ~50% of the observed inhibition, suggesting a deeper understanding of the underlying principals is still lacking. We suggest that naringenin exerts its metabolic, and consequently, antiviral effects through modulation of nuclear recepetor (NR) activity. NRs are a superfamily of ligand-regulated transcription factors known to have an important role in maintaining the homeostasis of metabolites. We show that naringenin activates peroxisome proliferator activated receptors (PPARs), NRs known to drive [beta]-oxidation; and inhibits the liver X receptor (LXR), known to drive lipogenesis and cholesterol synthesis. Despite naringenin;;s promise as a possible treatment for HCV, its low bioavailability, limits its clinical potential. We conclude this work by showing that naringenin;;s solubility and bioavailability - and thus, clinical relevance - can be greatly enhanced by complexation with [beta]-cyclodextrins.

[发布机构] Massachusetts Institute of Technology