Induction of p450 enzymes by derivative of parthenolide
10.7501/j.issn.0253-2670.2019.06.025
- Author:
Xiao-Yan CI
1
Author Information
1. State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research New Drug Evaluation Co., Ltd.
- Publication Type:Journal Article
- Keywords:
ACT001;
P450 induction;
Parthenolide;
Primary human liver adherent cells;
Sesquiterpene lactones
- From:
Chinese Traditional and Herbal Drugs
2019;50(6):1424-1429
- CountryChina
- Language:Chinese
-
Abstract:
Objective: In this study, primary cultured human hepatocytes were used to study the induction of P450 enzyme by the sesquiterpene lactone derivative ACT001, which provided reference for the clinical use of ACT001. Methods Three batches of frozen primary human hepatocytes were inoculated and cultured, and CYP1A2, CYP2B6 and CYP3A4 were induced by ACT001. Real-time fluorescence quantitative PCR was used to determine the mRNA expression level of P450 enzyme, and the activity of P450 enzyme was determined by LC-MS/MS method. Results The expression level of P450 enzyme mRNA and the activity of P450 enzyme showed that the P450 enzyme induction model was successfully established. Compared with the control group, the CYP1A2 mRNA expression level and enzyme activity of ACT001 1 μmol/L and 6 μmol/L group showed no significant changes. The mRNA expression level of CYP1A2 in ACT001 30 μmol/L group was significantly decreased, and the enzyme activity was decreased, but not as significantly as that of mRNA. With the increase of ACT001 concentration, the expression level of CYP2B6 mRNA was gradually increased. Compared with the control group, the expression level of CYP2B6 mRNA in the ACT001 group at 30 μmol/L was significantly increased, which was seven times higher than that in the control group, and the increase of enzyme activity was four times higher than that in the control group, which was 40% higher than that in the phenobarbital sodium induction multiple. Compared with the control group, the CYP3A4 mRNA expression level of cells in the ACT001 1 μmol/L group was significantly increased, which was four times higher than that of the control group, but did not reach 40% of the positive inducer rifampicin, and the CYP3A4 mRNA expression level was decreased gradually with the increase of ACT001 concentration. At the same time, there was no significant increase in CYP3A4 enzyme activity after ACT001 administration at different concentrations, which was less than two times of that in the control group. Conclusion The data indicated that ACT001 had no induction potential for CYP1A2 and CYP3A4, and had potential for CYP2B6 induction. In combination with CYP2B6 substrates, it should be avoided in clinical combination therapy to reduce adverse reactions caused by P450-mediated drug drug interaction.
