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Mechanism of the Inductive Effect of Zolmitriptan on Rat Hepatic CYP3A1/2

Author: XingFeng
Tutor: ZengSu；YuLuShan
School: Zhejiang University
Course: Pharmaceutical Analysis
Keywords: Zolmitriptan Cytochrome P450 CYP 3A Pregnane X receptor Gender differences
CLC: R96
Type: Master's thesis
Year: 2010
Downloads: 67
Quote: 0
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Abstract


Reporter gene, the subject of zolmitriptan induced hepatic CYP 3A1 / 2 mechanism study investigated the role of PXR in the induction process. And the team on the basis of previous experiments, the effects of zolmitriptan childhood SD rat liver CYP 3A2 protein expression and activity induced to study the zolmitriptan gender differences inducing rat hepatic CYP 3A1 / 2 generation mechanism. Objective To study the zolmitriptan induced CYP 3A1 / 2 mechanism and test Chazuo Mi triptans hepatic CYP3A2 induced trend with dose. The method of extracting the total mouse liver DNA as template for PCR amplification to obtain the promoter sequence of the CYP 3A1 / 2. These two sequences are respectively connected to a pMD18-T vector and DNA sequencing to select the correct sequence of the DNA sequence, connected to the pGL3 plasmid pGL3-3A1 promoter and the pGL3-3A2promoter plasmid. Will rPXR gene sequence and PCDNA3.1 of carrier connection plasmid construct rPXR-PCDNA3.1. Were pGL3-3A1 / 2 promoter the plasmid with rPXR-pcDNA3.1 plasmid pRL-TK certain proportion of transfected to HepG2 cells. Dosing for 24h, investigated by detecting the fluorescence intensity of the drug on the induction of CYP3A1 / 2 promoter sequence. 16α-cyano-inducing agent to the classic pregnenolone (PCN) as a positive control, a blank solvent (DMSO) as a negative control was observed for different concentrations of zolmitriptan (10,50,100 μmol · L -1 < / sup>) of rat liver CYP3A1 / 2 induction. Born 14 days for three days in a row of different gender pups ig 1ml, preparation of microsomes. Negative control group, positive control group, blank solvent CMC-Na group to 20mg/200g dexamethasone administered group as liver investigated different dose zolmitriptan (0.1,0.5 and 2.5mg/200g) of SD rats of different sex CYP 3A2 induced. Western Blot was investigated microsomal CYP 3A2 protein expression and testosterone for the activity of the substrate detection microsomal CYP 3A. For 3 consecutive days of adult rats orally with different doses of zolmitriptan (0.01,0.1,0.5,2.5,5 10mg/200g) Preparation of liver microsomes, testosterone substrate detected microsomes CYP 3A activity. As the positive control group, blank solvent CMC-Na group to 20mg/200g dexamethasone dose group and negative control group. Gene experiments compared with the negative control group, positive control group, zolmitriptan Tanzania 100μmol · L -1 metering group report on the results, a significant induction of hepatic CYP3A1 activity increased to 1.93, 1.96-fold; positive control group, zolmitriptan Tanzania 10μmol · L -1 50μmol · L -1 dose group of hepatic CYP3A2 induction effect, the activity increased to 2.51, 2.10 and 1.63 times. Zolmitriptan hepatic CYP3A2 protein content and activity in male and female rats were induced, and the middle dose (0.5mg/200g) and high dose (2.5mg/200g) induction of the male pups CYP 3A activity induced by a multiple of 2.20 and 1.85, respectively, female pups CYP 3A activity induced by a multiple of 1.71 and 1.55, respectively. Examine a range of doses of zolmitriptan induction of hepatic CYP 3A activity in male rats, induced dose for 0.5mg/200g, best induced multiple of 1.46. Conclusion the PXR path is zolmitriptan induced hepatic CYP3A1 / 2 is an important way. Zolmitriptan adult male rat liver CYP 3A induction of strong in adult female rats, this phenomenon due to the adult male rats contain two isoforms of CYP 3A1 and CYP 3A2 in the liver, while the adult female big contains only CYP 3A1 is a subtype of rat liver. Zolmitriptan male rat hepatic CYP 3A2 activity induced effect the first enhanced weakening trend with increasing dose.

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