Diterpene quinone tanshinone IIA selectively inhibits mouse and human cytochrome P4501A2

Yune Fang Ueng, Ya Hui Kuo, Hsiao Chi Peng, Ta Liang Chen, Woan Ching Jan, F. Peter Guengerich, Yun Lian Lin

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Abstract

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.

Original languageEnglish
Pages (from-to)603-613
Number of pages11
JournalXenobiotica
Volume33
Issue number6
DOIs
Publication statusPublished - Jun 1 2003
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Pharmacology
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Ueng, Y. F., Kuo, Y. H., Peng, H. C., Chen, T. L., Jan, W. C., Guengerich, F. P., & Lin, Y. L. (2003). Diterpene quinone tanshinone IIA selectively inhibits mouse and human cytochrome P4501A2. Xenobiotica, 33(6), 603-613. https://doi.org/10.1080/0049825031000105769