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Abstract
BackgroundSodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA for treating cardiovascular disorders. The roles of cytochrome P450 enzymes (CYPs) in the metabolism of STS have remained unclear. This study aims to screen the main CYPs for metabolism of STS and study their interactions in vitro.MethodsSeven major CYPs were screened for metabolism of STS by human liver microsomes (HLMs) or recombinant CYP isoforms. Phenacetin (CYP1A2), coumarin (CYP2A6), tolbutamide (CYP2C9), metoprolol (CYP2D6), chlorzoxazone (CYP2E1), S-mephenytoin (CYP2C19), and midazolam (CYP3A4) were used as probe substrates to determine the potential of STS in affecting CYP-mediated phase I metabolism in humans. Enzyme kinetic studies were performed to investigate the modes of inhibition of the enzyme–substrate interactions by GraphPad Prism Enzyme Kinetic 5 Demo software.ResultsSodium tanshinone IIA sulfonate inhibited the activity of CYP3A4 in a dose–dependent manner by the HLMs and CYP3A4 isoform. The Km and Vmax values of STS were 54.8 ± 14.6 µM and 0.9 ± 0.1 nmol/mg protein/min, respectively, for the HLMs and 7.5 ± 1.4 µM and 6.8 ± 0.3 nmol/nmol P450/min, respectively, for CYP3A4. CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, and CYP2C19 showed minimal or no effects on the metabolism of STS.ConclusionThis in vitro study showed that STS mainly inhibited the activities of CYP3A4.Electronic supplementary materialThe online version of this article (doi:10.1186/s13020-016-0083-z) contains supplementary material, which is available to authorized users.
Highlights
Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA for treating cardio‐ vascular disorders
Ueng et al [19] reported that tanshinone IIA could decrease 7-ethoxyresorufin O-deethylation (EROD) and 7-methoxyresorufin O-demethylation (MROD) activities in Ouyang et al Chin Med (2016) 11:11 a b human liver microsomes (HLMs), and indicated that tanshinone IIA possessed the highest selectivity for inhibition of CYP1A2.The same authors further demonstrated that tanshinone IIA induced hepatic Cyp1A2 by increasing the expression levels of Cyp1A2 mRNA and protein in mice [20]
Many experiments related to tanshinone IIA have been performed, the question of which cytochrome P450 enzymes (CYPs) is responsible for the metabolism of STS has remained unclear
Summary
Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA for treating cardio‐ vascular disorders. The roles of cytochrome P450 enzymes (CYPs) in the metabolism of STS have remained unclear. Tanshinone IIA (Fig. 1a) is one of the main extracts from Salvia miltiorrhiza (Danshen) for treating cardiovascular disorders [1]. Tanshinone IIA is the most effective fat-soluble monomer extracted from Danshen, with anti-inflammatory [2], antitumor [3], antioxidative [4, 5], and antiplatelet aggregation activities [6, 7]. Liu et al [21] reported that CYP2A6 was the specific isozyme responsible for hydroxyl metabolism of tanshinone IIA in HLMs. many experiments related to tanshinone IIA have been performed, the question of which CYP is responsible for the metabolism of STS has remained unclear
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