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1. Phytomedicine. 2012 Apr 26. [Epub ahead of print]

Molecular docking and enzyme kinetic studies of dihydrotanshinone on metabolism
of a model CYP2D6 probe substrate in human liver microsomes.

Zhou X, Wang Y, Or PM, Wan DC, Kwan YW, Yeung JH.

School of Biomedical Sciences, Faculty of Medicine, The Chinese University of
Hong Kong, Shatin, N.T., Hong Kong SAR, China.

The effects of Danshen and its active components (tanshinone I, tanshinone IIA,
dihydrotanshinone and cryptotanshinone) on CYP2D6 activity was investigated by
measuring the metabolism of a model CYP2D6 probe substrate, dextromethorphan to
dextrorphan in human pooled liver microsomes. The ethanolic extract of crude
Danshen (6.25-100μg/ml) decreased dextromethorphan O-demethylation in vitro
(IC(50)=23.3μg/ml) and the water extract of crude Danshen (0.0625-1mg/ml) showed
no inhibition. A commercially available Danshen pill (31.25-500μg/ml) also
decreased CYP2D6 activity (IC(50)=265.8μg/ml). Among the tanshinones, only
dihydrotanshinone significantly inhibited CYP2D6 activity (IC(50)=35.4μM),
compared to quinidine, a specific CYP2D6 inhibitor (IC(50)=0.9μM).
Crytotanshinone, tanshinone I and tanshinone IIA produced weak inhibition, with
IC(20) of 40.8μM, 16.5μM and 61.4μM, respectively. Water soluble components such
as salvianolic acid B and danshensu did not affect CYP2D6-mediated metabolism.
Enzyme kinetics studies showed that inhibition of CYP2D6 activity by the
ethanolic extract of crude Danshen and dihydrotanshinone was
concentration-dependent, with K(i) values of 4.23μg/ml and 2.53μM, respectively,
compared to quinidine, K(i)=0.41μM. Molecular docking study confirmed that
dihydrotanshinone and tanshinone I interacted with the Phe120 amino acid residue
in the active cavity of CYP2D6 through Pi-Pi interaction, but did not interact
with Glu216 and Asp301, the key residues for substrate binding. The logarithm of
free binding energy of dihydrotanshinone (-7.6kcal/mol) to Phe120 was comparable
to quinidine (-7.0kcal/mol) but greater than tanshinone I (-5.4kcal/mol),
indicating dihydrotanshinone has similar affinity to quinidine in binding to the
catalytic site on CYP2D6.

Copyright © 2012 Elsevier GmbH. All rights reserved.

PMID: 22541637 [PubMed - as supplied by publisher]