1. Inhibitory effects of celastrol on rat liver cytochrome P450 1A2, 2C11, 2D6, 2E1 and 3A2 activity.
- Author
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Sun, Min, Tang, Yu, Ding, Tonggui, Liu, Mingyao, and Wang, Xin
- Subjects
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ENZYME metabolism , *ALTERNATIVE medicine , *ANIMAL experimentation , *ANTINEOPLASTIC agents , *BIOLOGICAL models , *DOSE-effect relationship in pharmacology , *ENZYME inhibitors , *ENZYMES , *HIGH performance liquid chromatography , *MEDICINAL plants , *RATS , *PLANT extracts , *DESCRIPTIVE statistics , *IN vitro studies - Abstract
Abstract: 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 (10.2μM)>CYP3A2 (23.2μM)>CYP1A2 (52.8μM)>CYP2E1 (74.2μM)>CYP2D6 (76.4μM). 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 K i of 39.2μM, 7.05μM and 14.2μM, 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. [Copyright &y& Elsevier]
- Published
- 2014
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