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 6beta-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 microM); medium competitive inhibitors of CYP2C9 (K(i)=22-62 microM); medium competitive inhibitors of CYP2E1 (K(i)=3.67 microM) for tanshinone I and 10.8 microM for crytotanshinone; but weak competitive inhibitors of CYP3A4 (K(i)=86-220 microM). Dihydrotanshinone was a competitive inhibitor of human CYP1A2 (K(i)=0.53 microM) and CYP2C9 (K(i)=1.92 microM), a noncompetitive inhibitor of CYP3A4 (K(i)=2.11 microM) 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.
Wang
Xin
X
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China.
Cheung
Ching Mei
CM
Lee
Wayne Y W
WY
Or
Penelope M Y
PM
Yeung
John H K
JH
D045784:Abietanes; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065729:Cytochrome P-450 CYP2C9; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D041743:Herb-Drug Interactions; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology*; D020033:Protein Isoforms; D027561:Salvia miltiorrhiza / Q000737:chemistry*
D045784:Abietanes; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D004365:Drugs, Chinese Herbal; D010616:Phenanthrenes; D020033:Protein Isoforms; C021751:tanshinone; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human