Abstract
BackgroundHIV protease inhibitor (PI)-induced inflammatory response in macrophages is a major risk factor for cardiovascular diseases. We have previously reported that berberine (BBR), a traditional herbal medicine, prevents HIV PI-induced inflammatory response through inhibiting endoplasmic reticulum (ER) stress in macrophages. We also found that HIV PIs significantly increased the intracellular concentrations of BBR in macrophages. However, the underlying mechanisms of HIV PI-induced BBR accumulation are unknown. This study examined the role of P-glycoprotein (P-gp) in HIV PI-mediated accumulation of BBR in macrophages.Methodology and Principal FindingsCultured mouse RAW264.7 macrophages, human THP-1-derived macrophages, Wild type MDCK (MDCK/WT) and human P-gp transfected (MDCK/P-gp) cells were used in this study. The intracellular concentration of BBR was determined by HPLC. The activity of P-gp was assessed by measuring digoxin and rhodamine 123 (Rh123) efflux. The interaction between P-gp and BBR or HIV PIs was predicated by Glide docking using Schrodinger program. The results indicate that P-gp contributed to the efflux of BBR in macrophages. HIV PIs significantly increased BBR concentrations in macrophages; however, BBR did not alter cellular HIV PI concentrations. Although HIV PIs did not affect P-gp expression, P-gp transport activities were significantly inhibited in HIV PI-treated macrophages. Furthermore, the molecular docking study suggests that both HIV PIs and BBR fit the binding pocket of P-gp, and HIV PIs may compete with BBR to bind P-gp.Conclusion and SignificanceHIV PIs increase the concentration of BBR by modulating the transport activity of P-gp in macrophages. Understanding the cellular mechanisms of potential drug-drug interactions is critical prior to applying successful combinational therapy in the clinic.
Highlights
Human immunodeficiency virus (HIV) protease inhibitors (PIs) are the major components of highly active anti-retroviral therapy (HAART) and have been successfully used to control disease progression in HIV-1 patients
HIV PIs increase the concentration of BBR by modulating the transport activity of P-gp in macrophages
Induced cardiovascular disease (CVD) remain to be fully elucidated, sufficient evidence suggests that lipid accumulation, inflammation, and activation of endoplasmic reticulum (ER) stress are all involved in HIV PIinduced cardiovascular complications and metabolic syndromes[3,4,5,6,7]
Summary
Human immunodeficiency virus (HIV) protease inhibitors (PIs) are the major components of highly active anti-retroviral therapy (HAART) and have been successfully used to control disease progression in HIV-1 patients. Induced CVD remain to be fully elucidated, sufficient evidence suggests that lipid accumulation, inflammation, and activation of endoplasmic reticulum (ER) stress are all involved in HIV PIinduced cardiovascular complications and metabolic syndromes[3,4,5,6,7]. Our previous study indicated that inhibition of ER stress by BBR represents a key mechanism by which this molecule prevents the HIV PI-induced inflammatory response [16]. HIV protease inhibitor (PI)-induced inflammatory response in macrophages is a major risk factor for cardiovascular diseases. We have previously reported that berberine (BBR), a traditional herbal medicine, prevents HIV PIinduced inflammatory response through inhibiting endoplasmic reticulum (ER) stress in macrophages. This study examined the role of P-glycoprotein (P-gp) in HIV PI-mediated accumulation of BBR in macrophages
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