Major tanshinones of Danshen ( Salvia miltiorrhiza) exhibit different modes of inhibition on human CYP1A2, CYP2C9, CYP2E1 and CYP3A4 activities in vitro

This study investigated the effects of tanshinones on human CYP1A2 (phenacetin O-deethylase), CYP2C9 (tolbutamide 4-hydroxylase), CYP2E1 (chlorzoxazone 6-hydroxylase) and CYP3A4 (testosterone 6β-hydroxylase) activities in vitro using pooled human liver microsomes and specific human CYP isoforms. Tanshinone I, tanshinone IIA, and cryptotanshinone were potent competitive CYP1A2 inhibitors ( K i = 1.5–2.5 μM); medium competitive inhibitors of CYP2C9 ( K i = 22–62 μM); medium competitive inhibitors of CYP2E1 ( K i = 3.67 μM) for tanshinone I and 10.8 μM for crytotanshinone; but weak competitive inhibitors of CYP3A4 ( K i = 86–220 μM). Dihydrotanshinone was a competitive inhibitor of human CYP1A2 ( K i = 0.53 μM) and CYP2C9 ( K i = 1.92 μM), a noncompetitive inhibitor of CYP3A4 ( K i = 2.11 μM) but an uncompetitive CYP2E1 inhibitor. In conclusion, these results showed that tanshinones inhibited the metabolism of various CYP probe substrates in human liver microsomes and specific human CYP isoforms in vitro. Given that CYP1A2, 2C9, 2E1 and 3A4 are responsible for the metabolism and disposition of a large number of drugs currently used, the potential herb–drug interactions of Danshen preparations containing the major tanshinones with drugs which are substrates of these CYPs may be important.