Received for publication February 14, 2008.
Revised April 4, 2008.
Accepted for publication April 8, 2008.

Inhibitory effects of seven components of danshen extract on catalytic activity of cytochrome P450 enzymes in human liver microsomes

Abstract

The potential for herb-drug interactions has recently received greater attention worldwide, considering the fact that the use of herbal products becomes more and more widespread. The goal of this work was to examine the potential for the metabolism-based drug interaction arising from seven active components (danshensu, protocatechuic aldehyde, protocatechuic acid, salvianolic acid B, tanshinone I, tanshinone IIA and cryptotanshinone) of danshen extract. Probe substrates of CYP enzymes were incubated in HLMs with or without each component of danshen extract. IC₅₀ and K_i values were estimated and the types of inhibition were determined. Among the seven components of danshen extract, tanshinone I, tanshinone IIA, and cryptotanshinone were potent competitive inhibitors of CYP1A2 (K_i=0.48µM, 1.0µM, 0.45µM, respectively); danshensu was a competitive inhibitor of CYP2C9 (K_i=35µM), and cryptotanshinone was a moderate mixed type inhibitor of CYP2C9 (K_i=8µM); cryptotanshinone inhibited weakly and in mixed mode against CYP2D6 activity (K_i=68µM), and tanshinone I was a weak inhibitor of CYP2D6 (IC₅₀=120µM); protocatechuic aldehyde was a weak inhibitor of CYP3A4 (IC₅₀=130 µM, 160 µM for midazolam and testosterone, respectively). These findings provided some useful information for safe and effective use of danshen preparations in clinical practice. Our data indicated that it was necessary to study the in vivo interactions between drugs and pharmaceuticals with danshen extract.

Key words: drug interactions, enzyme inhibitors, enzyme kinetics, human CYP enzymes