Safety of Herbal Medicinal Products: Echinacea and Selected Alkylamides Do Not Induce CYP3A4 mRNA Expression

Michael Heinrich,Andy Suter,Andreas Kortenkamp,Elisabete Silva,Maryam Modarai

doi:10.1093/ecam/nep174

Abstract

A major safety concern with the use of herbal medicinal products (HMP) is their interactions with conventional medicines, which are often mediated via the cytochrome P450 (CYP) system. Echinacea is a widely used over-the-counter HMP, with proven immunomodulatory properties. Its increasing use makes research into its safety an urgent concern. Previously, we showed that Echinacea extracts and its alkylamides (thought to be important for Echinacea's immunomodulatory activity) mildly inhibit the enzymatic activity of the main drug metabolising CYP isoforms, but to this date, there is insufficient work on its ability to alter CYP expression levels. We now report for the first time the effect of a commercial Echinacea extract (Echinaforce) and four Echinacea alkylamides on the transcription of the major drug metabolizing enzyme CYP3A4. HepG2 cells were exposed for 96 h to clinically relevant concentrations of Echinaforce (22, 11.6 and 1.16 μg mL−1) or the alkylamides (1.62 and 44 nM). CYP3A4 mRNA levels were quantified using real-time reverse transcription polymerase chain reaction (RT-PCR). Neither Echinaforce nor the alkylamides produced any significant changes in the steady-state CYP3A4 mRNA levels, under these conditions. In contrast, treatment with 50 μM rifampicin resulted in a 3.8-fold up-regulation over the vehicle control. We conclude that Echinaforce is unlikely to affect CYP3A4 transcriptional levels, even at concentrations which can inhibit the enzymatic activity of CYP3A4. Overall, our data provides further evidence for the lack of interactions between Echinacea and conventional drugs.

Highlights

Interactions between herbal medicinal products (HMP) and conventional drugs are a major safety concern
For the alkylamides the clinically relevant concentrations were taken from Woelkart et al [18, 19], who found that alkylamide (1) reached the highest plasma concentration of 44 or 1.62 nM in human volunteers dosed with an E. angustifolia root extract and Echinaforce, respectively [18, 19]
The viability of HepG2 cells exposed to Echinaforce, ethanol or each of the alkylamides, for 96 h was investigated in the MTT assay

Summary

Introduction

Interactions between herbal medicinal products (HMP) and conventional drugs are a major safety concern. One of the main pathways for such interactions is via the cytochrome P450 (CYP) enzymes. Direct inhibition or induction of CYP isoforms by HMP can alter the metabolism of conventional drugs, leading to adverse effects. An example showcasing the significance of such interactions is St. John’s Wort, which has been shown to affect the pharmacokinetics of several important drugs [1], highlighting the need for in vitro investigations into the possible interactions of HMP with CYP isoforms [2]. We investigated in detail the ability of Echinacea to inhibit various CYP isoforms [6]. We showed that Echinacea and some of its alkylamides weakly inhibit a number of major CYP isoforms. We screened 10 commercially available Echinacea liquid preparations (ELP) for CYP3A4 inhibitory activity and found that it varied considerably (IC50 values 12.7–1817 μg mL−1) [6]

Methods

Results

Conclusion