Active Hydrophilic Components of the Medicinal HerbSalvia miltiorrhiza(Danshen) Potently Inhibit Organic Anion Transporters 1 (Slc22a6) and 3 (Slc22a8)

Li Wang,Douglas H Sweet

doi:10.1155/2012/872458

Abstract

Many active components of herbal products are small organic anions, and organic anion transporters were previously demonstrated to be a potential site of drug-drug interactions. In this study, we assessed the inhibitory effects of six hydrophilic components of the herbal medicine Danshen, lithospermic acid, protocatechuic acid, rosmarinic acid, salvianolic acid A, salvianolic acid B, and tanshinol, on the function of the murine organic anion transporters, mOat1 and mOat3. All of Danshen components significantly inhibited mOat1- and mOat3-mediated substrate uptake (P < 0.001) with lithospermic acid (LSA), protocatechuic acid, rosmarinic acid (RMA), and salvianolic acid A (SAA) producing virtually complete inhibition under test conditions. Kinetic analysis demonstrated that LSA, RMA, and SAA were competitive inhibitors. As such, K i values were estimated as 14.9 ± 4.9 μM for LSA, 5.5 ± 2.2 μM for RMA, and 4.9 ± 2.2 μM for SAA on mOat1-mediated transport, and as 31.1 ± 7.0 μM for LSA, 4.3 ± 0.2 μM for RMA, and 21.3 ± 7.7 μM for SAA on mOat3-mediated transport. These data suggest that herb-drug interactions may occur in vivo on the human orthologs of these transporters in situations of polypharmacy involving Danshen and clinical therapeutics known to be organic anion transporter substrates.

Highlights

The Chinese herbal medicine, Danshen (Salvia miltiorrhiza), has been employed for thousands of years in the relief of symptoms of cardiovascular disease [1,2,3]
Protocatechuic aldehyde is a major component in Danshen extracts whereas the protocatechuic acid level is insignificant), rosmarinic acid (RMA), salvianolic acid A (SAA), salvianolic acid B (SAB), and tanshinol (TSL), are gaining favor as the Danshen components responsible for the beneficial effects on heart disease [4,5,6]
An uptake assay with excess (1 mM) Danshen components was performed to identify which, if any, of the compounds might interact with mOat1 (Figure 2(a))

Summary

Introduction

The Chinese herbal medicine, Danshen (Salvia miltiorrhiza), has been employed for thousands of years in the relief of symptoms of cardiovascular disease [1,2,3]. Protocatechuic aldehyde is a major component in Danshen extracts whereas the protocatechuic acid level is insignificant), rosmarinic acid (RMA), salvianolic acid A (SAA), salvianolic acid B (SAB), and tanshinol (TSL), are gaining favor as the Danshen components responsible for the beneficial effects on heart disease [4,5,6]. Since these compounds are organic, small in size (154–718 Da), and exist as anions at physiological pH, it is possible that they are substrates and/or inhibitors of the organic anion transport pathway that exists in organs such as the kidney, liver, intestine, and choroid plexus [7]

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