TY - JOUR
T1 - Inhibitory effects of celastrol on rat liver cytochrome P450 1A2, 2C11, 2D6, 2E1 and 3A2 activity
AU - Sun, Min
AU - Tang, Yu
AU - Ding, Tonggui
AU - Liu, Mingyao
AU - Wang, Xin
PY - 2014/1
Y1 - 2014/1
N2 - The present study was the first time to investigate the effects of celastrol, derived from Trypterygium wilfordii Hook F. ("Thunder of God Vine"), a traditional Chinese medicine plant, on the metabolism of model probe substrates of CYP isoforms, CYP1A2, CYP2C11, CYP2D6, CYP2E1 and CYP3A2, which are important in the metabolism of a variety of xenobiotics. The effects of celastrol on CYP1A2 (phenacetin O-deethylase), CYP2C11 (tolbutamide 4-hydroxylase), CYP2D6 (dextromethorphan O-demethylation), CYP2E1 (chlorzoxazone 6-hydroxylase) and CYP3A2 (testosterone 6β-hydroxylase) activities were investigated using rat liver microsomes. HPLC-DAD was used to measure the model substrates and metabolites. Inhibition of rat CYP isoforms (IC50) by celastrol in potency order was CYP2C11 (10.2 μM) > CYP3A2 (23.2 μM) > CYP1A2 (52.8 μM) > CYP2E1 (74.2 μM) > CYP2D6 (76.4 μM). Enzyme kinetic studies showed that the celastrol was not only a competitive inhibitor of CYP1A2 and 2C11, but also a mixed-type inhibitor of CYP3A2, with Ki of 39.2 μM, 7.05 μM and 14.2 μM, respectively. The data indicate that celastrol inhibited the metabolism of CYP1A2, 2C and 3A substrates in rat liver in vitro with a different mode of inhibition. These in vitro studies of celastrol with CYP isoforms may be helpful for the development and application of celastrol as a promising anti-cancer agent. Further systematic studies in humans in vitro and in vivo are needed to identify the interactions of celastrol with cytochrome P450s.
AB - The present study was the first time to investigate the effects of celastrol, derived from Trypterygium wilfordii Hook F. ("Thunder of God Vine"), a traditional Chinese medicine plant, on the metabolism of model probe substrates of CYP isoforms, CYP1A2, CYP2C11, CYP2D6, CYP2E1 and CYP3A2, which are important in the metabolism of a variety of xenobiotics. The effects of celastrol on CYP1A2 (phenacetin O-deethylase), CYP2C11 (tolbutamide 4-hydroxylase), CYP2D6 (dextromethorphan O-demethylation), CYP2E1 (chlorzoxazone 6-hydroxylase) and CYP3A2 (testosterone 6β-hydroxylase) activities were investigated using rat liver microsomes. HPLC-DAD was used to measure the model substrates and metabolites. Inhibition of rat CYP isoforms (IC50) by celastrol in potency order was CYP2C11 (10.2 μM) > CYP3A2 (23.2 μM) > CYP1A2 (52.8 μM) > CYP2E1 (74.2 μM) > CYP2D6 (76.4 μM). Enzyme kinetic studies showed that the celastrol was not only a competitive inhibitor of CYP1A2 and 2C11, but also a mixed-type inhibitor of CYP3A2, with Ki of 39.2 μM, 7.05 μM and 14.2 μM, respectively. The data indicate that celastrol inhibited the metabolism of CYP1A2, 2C and 3A substrates in rat liver in vitro with a different mode of inhibition. These in vitro studies of celastrol with CYP isoforms may be helpful for the development and application of celastrol as a promising anti-cancer agent. Further systematic studies in humans in vitro and in vivo are needed to identify the interactions of celastrol with cytochrome P450s.
KW - Celastrol
KW - Competitive inhibitor
KW - Cytochrome P450 (CYP)
KW - Mixed-type inhibitor
UR - https://www.scopus.com/pages/publications/84887223533
U2 - 10.1016/j.fitote.2013.10.004
DO - 10.1016/j.fitote.2013.10.004
M3 - 文章
C2 - 24144799
AN - SCOPUS:84887223533
SN - 0367-326X
VL - 92
SP - 1
EP - 8
JO - Fitoterapia
JF - Fitoterapia
IS - 1
ER -
