TY - JOUR
T1 - Diterpene quinone tanshinone IIA selectively inhibits mouse and human cytochrome P4501A2
AU - Ueng, Yune Fang
AU - Kuo, Ya Hui
AU - Peng, Hsiao Chi
AU - Chen, Ta Liang
AU - Jan, Woan Ching
AU - Guengerich, F. Peter
AU - Lin, Yun Lian
N1 - Funding Information:
This paper was supported by National Research Institute of Chinese Medicine, Taipe i.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2003/6/1
Y1 - 2003/6/1
N2 - 1. Tanshinone IIA is the main active diterpene quinone in the herbal medicine Salvia miltiorrhiza. In untreated mouse liver microsomes, tanshinone IIA selectively inhibited 7-ethoxyresorufin O-deethylation (EROD) and 7-methoxyresorufin O-demethylation (MROD) activities without affecting the oxidation of benzo(a)pyrene, tolbutamide, N-nitrosodimethylamine and nifedipine. Tanshinone IIA was a competitive inhibitor of MROD activity with a Ki of 7.2 ± 0.7 nM. 2. In 3-methylcholanthrene-treated mouse liver microsomes, tanshinone IIA and two minor tanshinones, tanshinone I and cryptotanshinone, inhibited liver microsomal MROD activity without affecting EROD and benzo(a)pyrene hydroxylation activities at the concentrations up to 1 μM. Tanshinone IIA induced a type I binding spectrum with a spectral dissociation constant Ks of 2.3 ± 0.8 μM without cooperativity. 3. In human liver microsomes, tanshinone IIA decreased EROD and MROD activities without affecting the oxidation of benzo(a)pyrene, tolbutamide, chtorzoxazone and nifedipine. 4. In Escherichia coli membranes expressing bicistronic human CYP1A enzymes, tanshinone IIA inhibited EROD activity of CYP1A1 with an IC50 48 times higher than that for CYP1A2. Tanshinone I and cryptotanshinone had the same IC50 ratio (1A1/1A2) of 4. 5. The results indicate that tanshinone represents a new group of CYP1A inhibitors, and tanshinone IIA had the highest selectivity in inhibition of CYP1A2.
AB - 1. Tanshinone IIA is the main active diterpene quinone in the herbal medicine Salvia miltiorrhiza. In untreated mouse liver microsomes, tanshinone IIA selectively inhibited 7-ethoxyresorufin O-deethylation (EROD) and 7-methoxyresorufin O-demethylation (MROD) activities without affecting the oxidation of benzo(a)pyrene, tolbutamide, N-nitrosodimethylamine and nifedipine. Tanshinone IIA was a competitive inhibitor of MROD activity with a Ki of 7.2 ± 0.7 nM. 2. In 3-methylcholanthrene-treated mouse liver microsomes, tanshinone IIA and two minor tanshinones, tanshinone I and cryptotanshinone, inhibited liver microsomal MROD activity without affecting EROD and benzo(a)pyrene hydroxylation activities at the concentrations up to 1 μM. Tanshinone IIA induced a type I binding spectrum with a spectral dissociation constant Ks of 2.3 ± 0.8 μM without cooperativity. 3. In human liver microsomes, tanshinone IIA decreased EROD and MROD activities without affecting the oxidation of benzo(a)pyrene, tolbutamide, chtorzoxazone and nifedipine. 4. In Escherichia coli membranes expressing bicistronic human CYP1A enzymes, tanshinone IIA inhibited EROD activity of CYP1A1 with an IC50 48 times higher than that for CYP1A2. Tanshinone I and cryptotanshinone had the same IC50 ratio (1A1/1A2) of 4. 5. The results indicate that tanshinone represents a new group of CYP1A inhibitors, and tanshinone IIA had the highest selectivity in inhibition of CYP1A2.
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U2 - 10.1080/0049825031000105769
DO - 10.1080/0049825031000105769
M3 - Article
C2 - 12851037
AN - SCOPUS:0038772403
SN - 0049-8254
VL - 33
SP - 603
EP - 613
JO - Xenobiotica
JF - Xenobiotica
IS - 6
ER -
