Inhibitory Mechanisms of Celastrol on Human Liver Cytochrome P450 1A2, 2C19, 2D6, 2E1 and 3A4

1. The present study was conducted to examine the possibility of herb-drug interaction by celastrol, which is a main compound isolated from Tripterygium wilfordii Hook F. using human liver microsomes with cocktail methods. Focused on its inhibitory manner on the metabolism of model probe substrates of five cytochrome P450 isoenzymes (CYP1A2, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) in vitro which are important with the metabolism of different xenobiotics. 2. The results showed that celastrol inhibited the five types of human cytochrome P450 isoforms, with the IC50 values of 2.65 μM (CYP3A4), 5.99 μM (CYP2C19), 6.27 μM (CYP2D6), 7.66 μM (CYP1A2) and 9.38 μM (CYP2E1), respectively. The data indicated that celastrol acted in different manners as an inhibitor of human cytochrome P450 isoforms, which showed that celastrol not only un-competitively inhibited the CYP1A2 and 2E1 activities, but also competitively inhibited the CYP2C19 and 2D6 activities with Ki values of 1.41, 2.29, 5.27 and 4.21 μM, respectively. Celastrol was also a mixed-type inhibitor of CYP3A4, with Ki and Kis values of 2.02 and 5.49 μM, respectively. 3. Celastrol has the potential to inhibit cytochrome P450 activities and may cause the herb-drug interactions. Therefore, the use of celastrol and its preparations with conventional medicines should thus be taken in to account.