Inhibition of CYP1A1 by Quassinoids Found inPicrasma excelsa

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.

Cytochrome P450 Enzyme Inhibitors from Nature

“…To verify the accuracy of experimental techniques employed to detect CYP inhibition, assays with known inhibitors were carried out with furafylline (against CYP1A2), ketoconazole (against CYP1A1, CYP1B1 and CYP3A4), (−)-N-3-benzyl-phenobarbital (NBPB, against CYP2C19) and quinidine (against CYP2D6) and the obtained IC 50 values (0.8±0.2, 0.04±0.01, 6.3±1.7, 0.06±0.01, 0.3±191 0.01, and 0.03±0.01μM respectively) compared well with published values (0.99, b10, b10, 0.06, 0.25 and 0.01μM respectively; Shields, 2009;Badal et al, 2011;Powrie, 2010;Stresser et al, 2004;Cali, 2003 andMcLaughlin et al, 2008).…”

“…As such we unlocked the interaction between quassin and CYP1A1 in previous publication (Shields et al, 2009). One of the first active site models for CYP1A1 was demonstrated with quasin and important residues were highlighted; Asp313, Thr11, Ser124, Phe123, Ile386 and Leu496 as shown in Fig.7 as being critical for binding quassinoids.…”

“…Amyris plumieri is found in the Caribbean, Central America and Venezuela and plants of this genus have been used in folk medicine against skin irritation while isolates have been found to exhibit anticancer and antimycobacterial properties (Fuente et al, 1991, Hartwell, 1968. Even though both Peperomia amplexicaulis and Spathelia sorbifolia are not commonly consumed in Jamaica, isolates from these plants have been shown to exhibit antiprotozoal, chemopreventive and anti-cancer activity (Mota et al, 2009;Cassady et al, 1990) and previously examined for CYP inhibitions (Badal et al, 2011;Shields et al, 2009) and overviewed in this chapter. 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.…”

Possible mechanisms of action of the aqueous extract ofArtocarpus altilis(breadfruit) leaves in producing hypotension in normotensive Sprague–Dawley rats

“…The aqueous extract of A. altilis inhibited CYPs3A4 and 2D6 enzyme activities in the sub mg/mL levels, which appear to be poor in potency. Other medicinal plant extracts have been noted to have IC 50 values ranging between 0.1 mg/mL (Shields et al, 2009) and more potent values of less than 0.01 mg/mL (Tam et al, 2009;Agbonon et al, 2010). Although conclusive determinations can only be drawn from clinical studies, the weak inhibition displayed by the A. altilis extract in this in vitro investigation is indicative of a fairly low likelihood of clinically observable adversities through CYPs3A4 and 2D6 mediated metabolism.…”

Simaroubaceae family: botany, chemical composition and biological activities

“…Canthinone alkaloids and terpenoids can also elicit this kind of activity (Rivero-Cruz et al, 2005). In this context, Shields et al (2009) found that quassin and neoquassin inhibited the CYP1A1 isoenzyme, an isoform of the P450 cytochrome enzyme known for its carcinogenic activity, consequently assuming an important role as a chemoprotector (Shields et al, 2009). Simalikalactone D has also demonstrated a promising cytotoxic activity against mammary human adenocarcinoma cells .…”