Effect of African potato (Hypoxis hemerocallidea) extracts and its constituents on PXR and CYP450 Enzymes

Authors: HARON, MONA - University Of Mississippi; DALE, OLIVIA - University Of Mississippi; ZULFIQAR, FAZILA - University Of Mississippi; WANG, YAN HONG - University Of Mississippi; CHITTIBOYINA, AMAR - University Of Mississippi; KHAN, IKHLAS - University Of Mississippi; KHAN, SHABANA - University Of Mississippi

Submitted to: Applied In Vitro Toxicology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/13/2019
Publication Date: 3/13/2019
Citation: Haron, M.H., Dale, O.R., Zulfiqar, F., Wang, Y., Chittiboyina, A.G., Khan, I.A., Khan, S.I. 2019. Effect of African potato (Hypoxis hemerocallidea) extracts and its constituents on PXR and CYP450 Enzymes. Applied In Vitro Toxicology. 5(1):26-33. https://doi.org/10.1089/aivt.2018.0022.
DOI: https://doi.org/10.1089/aivt.2018.0022

Interpretive Summary: In recent years, there has been a rapid increase in the use of herbal dietary supplements (HDS) among adult Americans, which is also associated with an increased number of adverse effect including reports of drug-induced liver injury due to HDS consumption. The modulation of drug metabolizing regulators e.g. pregnane X receptor (PXR) and cytochrome P450 (CYPs) enzymes activity is responsible for most of the clinically relevant herb-drug interaction. Several herbs exhibit the potential to inhibit or induce various CYP isoforms due to a complex mixture of phytochemicals present in them. African potato (AP), indigenous to South Africa, is used traditionally for immune enhancement among other conditions. Although, the use of AP is popular among HIV/ AIDS and cancer patients, who are also on other therapies at the same time, the safety of such concomitant use has not been fully assessed. The purpose of this study is to determine the effects of a hydro-ethanolic extract of AP and its ethyl acetate and n-butanol fractions along with four isolated biologically relevant compounds (hypoxoside, hypoxhemeroloside A, acuminoside and obtuside A) on the transcriptional activity of PXR and catalytic activity of four major drug metabolizing CYP450 enzymes (CYP3A4, CYP1A2, CYP2C19 and CYP2D6). Our results showed a lack of PXR activation which indicates that H. hemerocallidea does not pose any risk to affect the expression of CYPs and P-gp. However, an inhibition of the catalytic activity of CYPs by the extract and its constituents was detected, which can affect the metabolism of conventional drugs when taken at the same time.

Technical Abstract: Introduction: Herb-drug interaction (HDI) is an important clinical risk associated with the concomitant consumption of herbal supplements with conventional drugs. African potato (AP) (Hypoxis hemerocallidea) is widely used by HIV and cancer patients as an immune enhancer. In this study we determined the effects of AP hydro-ethanolic extract, its ethyl acetate and n-butanol fractions and four of its major constituents (hypoxhemeroloside, hypoxide, acuminoside, and obtuside A) on the key regulators of drug metabolism and transport namely pregnane X receptor (PXR) and cytochrome P450 enzymes (CYP3A4, 2C19, 1A2 and 2D6) through in vitro methods. Materials and methods: A reporter gene assay was used to determine the activation of PXR. The inhibition of catalytic activity of CYPs was determined using recombinant enzymes. Chemical analysis of AP extract and its fractions was done by Ultra-High Performance Liquid Chromatography-Mass Spectrometry (UHPLC-MS). Results: No induction in the PXR transcriptional activity was observed with the AP extract or its constituents. AP extract inhibited CYP 2C19 while the ethyl acetate fraction inhibited CYP3A4, CYP2C19 and CYP1A2. n-butanol fraction showed weak inhibition of CYP3A4 and 2D6. Among the constituents, hypoxhemeroloside inhibited CYP2D6 and CYP1A2 while obtuside A inhibited CYP2C19 and CYP3A4. Conclusion: A lack of PXR activation indicates that H. hemerocallidea does not pose any risk to affect the expression of CYPs and P-gp. However, inhibition of catalytic activity of CYPs by the extract and its constituents may need further attention to assess the drug interaction potential of H. hemerocallidea.