Induction of cytochrome P450-dependent monooxygenase by extracts of the medicinal herbSalvia miltiorrhiza

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Abstract
The herbal medicine Salvia miltiorrhiza (Danshen) is currently used for the treatment of cardiovascular and cerebrovascular diseases. To assess possible herb-drug interactions, the effects of the aqueous and ethyl acetate extracts of S. miltiorrhiza on cytochrome P450 (CYP) were studied. Oral treatment of C57BL/6J mice with the ethyl acetate extract caused a dose-dependent increase in liver microsomal 7-methoxyresorufin O-demethylation (MROD) activity. The ethyl acetate extract caused an 8-, 2-, 3- and 3-fold increase in hepatic MROD, tolbutamide hydroxylation, nifedipine oxidation and warfarin 7-hydroxylation activity, respectively. However, the aqueous extract had no effects on any of the activities determined. Pharmaceutical product of S. miltiorrhiza extract caused a dose-dependent increase in MROD activity without affecting other activity. Immunoblot analysis of microsomal proteins showed that ethyl acetate extract-treatment elevated the protein levels of CYP1A and CYP3A. Tanshinone IIA was the main diterpene quinone in S. miltiorrhiza. At the dose corresponding to its content in ethyl acetate extract, tanshinone IIA-treatment increased mouse liver microsomal MROD activity. These results demonstrated that there were mouse CYP1A, CYP2C and CYP3A-inducing agents present in the ethyl acetate extract, but not in the aqueous extract, of S. miltiorrhiza. Tanshinone IIA played a role in the induction of CYP1A by S. miltiorrhiza. The CYP induction by the ethyl acetate extract and pharmaceutical product suggested that possible drug interactions between S. miltiorrhiza and CYP substrates should be noticed.