Isolation, synthesis, and drug interaction potential of secondary metabolites derived from the leaves of miracle tree (Moringa oleifera) against CYP3A4 and CYP2D6 isozymes

Phytomedicine. 2019 Jul:60:153010. doi: 10.1016/j.phymed.2019.153010. Epub 2019 Jul 2.

Abstract

Background: Moringa oleifera Lam. is known as a drumstick tree that is widely cultivated in various subtropical and tropical provinces. Previous studies indicated that both aqueous and methanolic extracts of M. oleifera leaves have potent inhibitory effects on two major drug metabolizing Cytochrome P450 enzymes, namely, CYP3A4 and CYP2D6.

Purpose: The current study was aimed to isolate the secondary metabolites from M. oleifera and investigate their cytotoxicity and inhibitory effects on CYP3A4 and CYP2D6 to assess their herb-drug interaction (HDI) potential.

Methods: Chemical structure elucidation was achieved by interpreting the spectroscopic data (UV, IR, 1D, and 2D NMR experiments), confirming by HR-ESI-MS, and comparing with the previously reported data in the literature. All the isolates were evaluated for their cytotoxicity against a panel of cell lines (SK-MEL, KB, BT-549, SK-OV-3, VERO, LLC-PK1, and HepG2) and inhibition of two principal CYP isozymes (CYP3A4 and CYP2D6).

Results: Phytochemical investigation of M. oleifera leaves resulted in the isolation and characterization of one new compound, namely omoringone (1), along with twelve known secondary metabolites (2-13) belonging to several chemical classes including flavonoids, terpenoids, lignans, and phenylalkanoids. A plausible biosynthetic pathway for compound 1 was provided. Because of the low isolation yield and limited supply, omoringone (1) and niazirin (12) were successively synthesized. No cytotoxicity was observed on any of the tested cell lines up to 50 µM. The extract exhibited an inhibitory effect on CYP3A4 isoform (IC50 = 52.5 ± 2.5 µg/ml). Among the isolates, 1-4 and 7-9 inhibited CYP3A4 with the IC50 values ranging from 41.5 to 100 µM with no remarkable effect on CYP2D6 isozyme.

Conclusion: This work aided in ascertaining components of M. oleifera contributing to CYP3A4 inhibition exhibited by the extract using an in vitro assay. Nonetheless, further studies are warranted to determine the bioavailability of the phytochemicals and extrapolate these findings in more physiologically relevant conditions to further establish the clinical relevance of in vitro observations.

Keywords: CC, column chromatography; CYP inhibition; CYP450, cytochrome P450; Cytotoxicity; HDI, herb-drug interaction; M. oleifera, Moringa oleifera; MeOH, methanol; Moringa oleifera; Moringaceae; Niazirin; Rhamnopyranoside synthesis.

MeSH terms

  • Cytochrome P-450 CYP2D6 / drug effects*
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP3A / drug effects*
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors
  • Herb-Drug Interactions*
  • Humans
  • Isoenzymes / drug effects
  • Moringa oleifera / chemistry*
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology*
  • Plant Leaves / chemistry
  • Trees

Substances

  • Cytochrome P-450 CYP3A Inhibitors
  • Isoenzymes
  • Plant Extracts
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human