Detoxification mechanism of promotion of drug clearance by activation of pregnane X receptor in situation of drug overdose
10.13699/j.cnki.1001-6821.2018.04.017
- VernacularTitle:药物过量时激活核受体孕烷X受体促进毒物消除的解毒机制
- Author:
Li-Bo DAI
1
;
Ping-Fei FANG
;
Huan-De LI
Author Information
1. 内蒙古自治区人民医院药学处
- Keywords:
pregnane X receptor;
P-glycoprotein;
drug metabolizing enzyme;
drug overdose rescue
- From:
The Chinese Journal of Clinical Pharmacology
2018;34(4):454-457
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the effects of regular dose and toxic dose of quetiapine (QTP) on PXR signaling and downstream CYP3A4 and P-gp mRNA expression in rat brain and liver and also further investigate the effects of PXR agonist (dexamethasone,DEX) on the mRNA expression of PXR,CYP3A4 and P-gp in these tissues in context of drug overdose to illustrate the potential detoxication mechanisms of PXR activation in the brain and liver.Methods Normal group was intraperitoneally injected with QTP 10 mg · kg-1 once,intoxication modeling group was intraperitoneally injected with QTP 100 mg · kg-1 once,and the PXR activation experimental group was intraperitoneally injected with DEX 2.5 mg · kg-1 · d-1 for consecutive 4 days.SD rats were randomly divided into 4 groups:blank group,normal group,model group,and experimental group.SD rats were dosed daily by the vehicle or dexamethasone 2.5 mg · kg-1 · d-1 for 4 days,and were intraperitoneally injected with the vehicle or QTP 10 or 100 mg · kg-1 on the fourth day.After the 4 days of drug treatment,the rats were sacrificed 12,24,48 h after the last dose.The mRNA expression of PXR,cytochrome P4503A4(CYP3A4) and P-glycoprotein (P-gp) of rats in 4 groups were assessed by Real-time PCR method.Results After administration QTP for 24 h,the expression of PXR mRNA in liver in blank group,normal group,model group,and experimental group were (15.8 ± 0.8) × 10-3,(27.8 ± 2.4) × 10-3,(33.3 ± 1.4) × 10-3,(49.2 ± 2.0) × 10-3,the difference between blank group and normal group was statistically significant (P ＜ 0.05),the difference between normal group and model group was statistically significant (P ＜ 0.05),and the difference between model group and experimental group was statistically significant (P ＜ 0.05).The factors in CYP3A4 and P-gp in liver of rats were same with PXR in liver,and the factors in prefrontal cortex and hippocampus of rats were same with in liver.Our data showed that QTP dose-dependently increased the expression of PXR,CYP3A4 and P-gp in both brain and liver.In addition,we found that the combination use of DEX along with the toxic dose of QTP accelerated the drug-induced mRNA expression of PXR,CYP3A4 and P-gp.Conclusion QTP itself could induce the signaling pathway of PXR-CYP3A4/P-gp,which was accelerated by the adjunctive use of PXR agonist,indicating that activation of PXR signaling pathway could activate detoxification system quickly and effectively,resulting in quick detoxification of xenobiotic and protection of organs.
