Interaction of Phytocompounds of Echinacea purpurea with ABCB1 and ABCG2 Efflux Transporters

Abstract

Preparations of Echinacea purpurea (E. purpurea) are widely used for the management of upper respiratory infections, influenza, and common cold, often in combination with other conventional drugs. However, the potential of phytochemical constituents of E. purpurea to cause herb–drug interactions via ABCB1 and ABCG2 efflux transporters remains elusive. The purpose of this study was to investigate the impact of E. purpurea-derived caffeic acid derivatives (cichoric acid and echinacoside) and tetraenes on the mRNA and protein expression levels as well as on transport activity of ABCB1 and ABCG2 in intestinal (Caco-2) and liver (HepG2) cell line models. The safety of these compounds was investigated by estimating EC20 values of cell viability assays in both cell lines. Regulation of ABCB1 and ABCG2 protein in these cell lines were analyzed after 24 h exposure to the compounds at 1, 10, and 50 μg/mL. Bidirectional transport of 0.5 μg/mL Hoechst 33342 and 5 μM rhodamine across Caco-2 monolayer and profiling for intracellular concentrations of the fluorophores in both cell lines were conducted to ascertain inhibition effects of the compounds. Cichoric acid showed no cytotoxic effect, while the EC20 values of tetraenes and echinacoside were 45.0 ± 3.0 and 52.0 ± 4.0 μg/mL in Caco-2 cells and 28.0 ± 4.3 and 62.0 ± 9.9 μg/mL in HepG2 cells, respectively. In general, the compounds showed heterogeneous induction of ABCB1 with the strongest 3.6 ± 1.2-fold increase observed for 10 μg/mL tetraenes in Caco-2 cells (p < 0.001). However, the compounds did not induce ABCG2. None of the phytocompounds inhibited significantly net flux of the fluorophores across Caco-2 monolayers. Overall, tetraenes moderately induced ABCB1 but not ABCG2 in Caco-2 and HepG2 cells while no compound significantly inhibited activity of these transporters at clinically relevant concentration to cause herb–drug interactions.

Evaluation of the Herb–Drug Interaction (HDI) Potential of Zingiber officinale and Its Major Phytoconstituents

“…Several transporter isoforms within the ATP-binding cassette (ABC) and solute carrier superfamilies have a vital role in drug absorption, distribution, and elimination. Recent research advocates that ABC transporters are synergistically activated or inhibited along with CYPs , and can intensify the magnitude of an HDI . Our RT-PCR analysis indicated that ginger extract and its phytochemicals moderately inhibited the expression of ABCB1/P-gp in both LS174T and HepG2 cells.…”

“…Recent research advocates that ABC transporters are synergistically activated or inhibited along with CYPs 18, 44 and can intensify the magnitude of an HDI. 46 Our RT-PCR analysis indicated that ginger extract and its phytochemicals moderately inhibited the expression of ABCB1/P-gp in both LS174T and HepG2 cells. Follow-up uptake assays showed that both extract and phytochemicals marginally increased the uptake of Rh-123 in both cell lines.…”

Natural Product – Drug Interactions and Their Evaluation Using a Caco-2 Cell Culture Model

“…On the other hand, in another Caco-2 cell study with E purpurea , derived active compounds cichoric acid, echinacoside, and tetraenes did not induce P-gp. 125 The results indicate that the compounds in an echinacea extract might have synergistic effects. Moreover, clinically, the effect of a concomitant medication could increase due to echinacea's effects on metabolizing CYP enzymes.…”

Echinacea purpurea: An overview of mechanism, efficacy, and safety in pediatric upper respiratory infections and otitis media

“…4.1. Immune-modulating E. purpurea contains a diverse array of bioactive compounds, including alkamides, caffeic acid derivatives, polysaccharides, and glycoproteins, which are believed to underlie its immunostimulatory properties (Awortwe et al, 2021;Balciunaite et al, 2020;de Oliveira et al, 2021;Ren et al, 2023;Vieira et al, 2023). These ingredients have been shown to have the ability to activate both cellular and humoral immunity by increasing the production and activation of white blood cells, lymphocytes, monocytes, and cytokines (Declerck et al, 2021;Khalaf et al, 2019).…”