In vitro inhibition of CYP3A4 and CYP2D6 activity by the horse chestnut constituents’ aescin and aesculetin
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1
Aristotle University of Thessaloniki, Department of Pharmacognosy and Pharmacology, Greece
Introduction. Herbal medicinal products (HMPs) are capable of modulating the metabolism through CYPs of several drugs. Horse chestnut seed extract (HCSE) derived from Aesculus hippocastanum has been found to inhibit CYP3A4 activity (Hellum and Nilsen, 2008). The aim of this study was to investigate two of the constituents of HCSE, aescin and aesculetin, for their in vitro inhibitory potential of CYP3A4 and CYP2D6. Aescin is the pharmacologically active compound of the herb and aescin is a secondary compound without attributed therapeutic properties.
Methods. Dextromethorphan was used as a probe drug to simultaneously assess CYP3A4 and CYP2D6 activity. Incubations of recombinant CYPs and analysis of the formed metabolites, 3-methoxymorphinan trough CYP3A4 and dextrorphan through CYP2D6, were conducted as previously described using a validated SIM GC/MS method (Spanakis et al., 2009). Results: The mean basic control activity of dextromethorphan metabolism was estimated to be 820 ± 58 pmol/CYP pmol/min for CYP3A4 and 75.5 ± 3.7 pmol/CYP pmol/min for CYP2D6. The estimated IC50 values for aescin were 12.1 ± 1.6 μΜ for CYP3A4 and 24.3 ± 5.3 μΜ for CYP2D6 and for aesculetin were 6.18 ± 1.3 μΜ for CYP3A4 and 39.2 ± 5.7 μΜ for CYP2D6, respectively.
Conclusion. The results of the present study showed that aesculetin is a more potent inhibitor of CYP3A4 than aescin suggesting that it may also contribute to the previously observed CYP3A4 inhibitory effect found for HCSE. Moreover, both compounds showed to be inhibitors of CYP2D6.
References
1. Hellum BH, Nilsen OG (2008) In vitro inhibition of CYP3A4 metabolism and P-glycoprotein-mediated transport by trade herbal products. Basic Clin Pharmacol Toxicol 102:466-475.
2. Spanakis M, Vizirianakis IS, Mironidou-Tzouveleki M, Niopas I (2009) A validated SIM GC/MS method for the simultaneous determination of dextromethorphan and its metabolites dextrorphan, 3-methoxymorphinan and 3-hydroxymorphinan in biological matrices and its application to in vitro CYP2D6 and CYP3A4 inhibition study. Biomed Chromatogr 23:1131-1137.
Keywords:
aescin,
aesculetin,
CYP3A4,
CYP2D6 activity
Conference:
8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010, Thessaloniki, Greece, 1 Oct - 5 Oct, 2010.
Presentation Type:
Poster
Topic:
Xenobiotic metabolism
Citation:
Spanakis
M,
Vizirianakis
IS,
Mironidou-Tzouveleki
M and
Niopas
I
(2010). In vitro inhibition of CYP3A4 and CYP2D6 activity by the horse chestnut constituents’ aescin and aesculetin.
Front. Pharmacol.
Conference Abstract:
8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010.
doi: 10.3389/conf.fphar.2010.60.00199
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Received:
07 Mar 2011;
Published Online:
04 Nov 2010.
*
Correspondence:
Dr. Ioannis Niopas, Aristotle University of Thessaloniki, Department of Pharmacognosy and Pharmacology, Thessaloniki, Greece, niopas@pharm.auth.gr