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Publication Type
Journal Article
Author, Analytic
Shields, M. ; Niazi, U. ; Badal, S. ; Yee, T. ; Sutcliffe, M. J. ; Delgoda, R.
Author Affiliation, Ana.
n/a
Article Title
Inhibition of CYP1A1 by Quassinoids Found in Picrasma excelsa
Medium Designator
n/a
Connective Phrase
n/a
Journal Title
Planta Med
Translated Title
n/a
Reprint Status
n/a
Date of Publication
2009 Feb
Volume ID
75
Issue ID
2
Page(s)
137-41
Language
eng
Connective Phrase
n/a
Location/URL
19016402
ISSN
0032-0943 (Print)
Notes
n/a
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 microM and 11.9 microM for quassin and neoquassin, respectively. The moderate inhibition against the CYP1A1 isoform by quassin and neoquassin displayed partial competitive inhibition kinetics, with inhibition constants ( K(i)) of 10.8 +/- 1.6 microM, for quassin and competitive inhibition kinetics, with a K(i) of 11.3 +/- 0.9 microM, 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.....
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