Inhibitory Effects of Danshen components on CYP2C8 and CYP2J2.

The use of Chinese herbal medicines and natural products has become increasingly popular in both China and Western societies as an alternative medicine for the treatment of diseases or as a health supplement. Danshen, the dried root of Salvia miltiorrhiza (Fam.Labiatae), which is rich in phenolic acids and tanshinones, is a widely used herbal medicine for the treatment of cardio-cerebrovascular diseases. The goal of this study was to examine the inhibitory effects of fifteen components derived from Danshen on CYP2C8 and CYP2J2, which are expressed both in human liver and cardiovascular systems. Recombinant CYP2C8 and CYP2J2 were used, and the mechanism, kinetics, and type of inhibition were determined. Taxol 6-hydroxylation and astemizole O-desmethyastemizole were determined as probe activities for CYP2C8 and CYP2J2, respectively. Metabolites formations were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results demonstrated that salvianolic acid A was a competitive inhibitor of CYP2C8 (Ki = 2.5 µM) and mixed-type inhibitor of CYP2J2 (Ki = 7.44 µM). Salvianolic acid C had moderate noncompetitive and mixed-type inhibitions on CYP2C8 (Ki = 4.82 µM) and CYP2J2 (Ki = 5.75 µM), respectively. Tanshinone IIA was a moderate competitive inhibitor of CYP2C8 (Ki = 1.18 µM). Dihydrotanshinone I had moderate noncompetitive inhibition on CYP2J2 (Ki = 6.59 µM), but mechanism-based inhibition on CYP2C8 (KI = 0.43 µM, kinact = 0.097 min-1). Tanshinone I was a moderate competitive inhibitor of CYP2C8 (Ki = 4.20 µM). These findings suggested that Danshen preparations appear not likely to pose a significant risk of drug interactions mediated by CYP2C8 after oral administration; but their inhibitory effects on intestinal CYP2J2 mediated drug metabolism should not be neglected when they are given orally in combination with other drugs. Additionally, this study provided novel insights into the underling pharmacological mechanisms of Danshen components from the perspective of CYP2C8 and CYP2J2 inhibition.