Inhibition of CYP1A1 by quassinoids found in Picrasma excelsa

Author Mario Shields, Umar Niazi, Simone Badal, Trevor Yee, Michael J. Sutcliffe, Rupika Delgoda*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Infusions of the plant Picrasma excelsa, known as Jamaican bitterwood tea, are commonly consumed to lower blood sugar levels in diabetics who are already on prescription medicines. We therefore investigated the inhibition properties of this tea against a panel of cytochrome P450 (CYP) enzymes, which are primarily responsible for the metabolism of a majority of drugs on the market. The two major ingredients, quassin and neoquassin, were then isolated and used for further characterization. Inhibition of the activities of heterologously expressed CYP microsomes (CYPs 2D6, 3A4, 1A1, 1A2, 2C9, and 2C19) was monitored, and the most potent inhibition was found to be against CYP1A1, with IC 50 values of 9.2 μM and 11.9 μM for quassin and neoquassin, respectively. The moderate inhibition against the CYP1A1 isoform by quassin and neoquassin displayed partial competitive inhibition kinetics, with inhibition constants (Ki) of 10.8±1.6 μM, for quassin and competitive inhibition kinetics, with a Ki of 11.3 ± 0.9 μM, for neoquassin. We then docked these two inhibitors into the active site of a model of CYP1A1, which provided insight at the atomic level into the structure-activity relationship of quassinoids with respect to this important CYP isoform known to be an activator of carcinogens, thus providing a useful basis for the search for more potent inhibitors of CYP1A1 that may have implications in chemoprotection.

Original languageEnglish (US)
Pages (from-to)137-141
Number of pages5
JournalPlanta Medica
Volume75
Issue number2
DOIs
StatePublished - Feb 2009

Keywords

  • CYP1A1
  • CYP1A2
  • Cytochrome P450
  • Picrasma excelsa
  • Quassinoids
  • Simaroubaceae

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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