Examining dietary supplements containing Euterpe oleracea Mart. (açaí) for potential botanical-drug interactions involving CYP3A4 inhibition

Abstract

BackgroundBotanical dietary supplements (BDS) are consumed more by cancer patients than otherwise healthier patients to alleviate side effects of chemotherapy drugs or increase quality of life. The enzyme responsible for the metabolism of most anticancer drugs is CYP3A4, an enzyme predominantly located in the liver. HypothesisOur research team examined the potential risk between CYP3A4-interactive cancer drugs and Euterpe oleracea Mart. (açaí) berry and found that the compounds that passively and non-passively diffused from methanol açaí extract displayed significant inhibition of liver CYP3A4 – suggesting the potential for interactions between açaí and drugs metabolized by CYP3A4 if used synchronously. This study aims to identify the compounds responsible for the CYP3A4 inhibition using the newly automated Bioactivity – Global Natural Product Social Molecular Networking (GNPS) tool. MethodsDietary supplement capsules from two manufacturers (F1 and F2) containing aqueous extracts of açaí fruits were extracted separately by methanol (ME) and acidic methanol (AC) and standardized to cyanidin-3-O-glucoside (CG) concentration at a human-relevant dose. After solvent removal, a parallel artificial membrane permeability assay (PAMPA) was utilized to filter intestinal passive diffusion of the four extract constituents so that compounds could be tested for inhibition of hepatic CYP3A4. Passively and non-passively diffused constituents of extracts from PAMPA assays were injected into the liquid chromatography-mass spectrometry (LC–MS) and characterized for visualization and comparison of chemical entities. To elucidate the non-passively diffused compounds responsible for significant CYP3A4 inhibition, the Bioactivity – GNPS tool was used to hypothesize which compounds within the formulation extract were potentially active to accelerate their identification. ResultsThere was no significant inhibition of CYP3A4 by passively diffused constituents for any extract. There was, however, significant inhibition by non-passively diffused constituents of both F1ME and F1AC extracts with 50 % CYP3A4 inhibition at the donor compartment concentrations 5.764 and 15.58 ng/ml CG, respectively. Six compounds were predicted to be inhibitors of CYP3A4 from methanol F1 extract, including betaine and 5 unknown compounds. ConclusionThis indicates that BDS containing açaí may not inhibit CYP3A4 through passively diffused compounds. Compounds from açaí BDS that inhibit CYP3A4 may be absorbed through other mechanisms, such as transporters.