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

Abstract

Hepatitis C virus (HCV) infection accounts for approximately 40% of chronic liver disease in the United States and results in an estimated 8,000-10,000 deaths annually. Simulations suggest that in the next decade morbidity and mortality associated with HCV infections will result in approximately 200,000 deaths and direct medical expenditures of over $10 billion. Furthermore, recent WHO estimates of worldwide prevalence suggest that up to 2% of the world population is infected with HCV, representing between 120 and 200 million people. For reasons that are still poorly understood, the current standard of care is effective only in a subset of patients, and depends on both patient-related and disease-related characteristics. Sustained virological response (SVR) - HCV RNA in patient plasma drops below detectable levels at week 24 following completion of treatment, which is thought to be indicative of curing the disease - is attainable in only ~50% of patients. In recent years, HCV production has been shown to be inextricably linked to lipid metabolism and to the secretion of very low density lipoproteins (VLDL) from hepatocytes. This suggests that by modulating lipid metabolism in the cell, viral production may be reduced in a clinically relevant manner.

(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.