國家衛生研究院 NHRI:Item 3990099045/5743
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    題名: Genetic polymorphisms of CYP2C19 associated with the side effect and serum concentrations of antidepressant paroxetine
    作者: Chan, HW;Tsou, HH;Tian, JN;Lin, KM;Hsiao, MC;Shen, WW;Lu, ML;Tang, HS;Fang, CK;Wu, CS;Lu, SC;Liu, SC;Chen, CY;Liu, YL
    貢獻者: Division of Mental Health and Addiction Medicine;Division of Biostatistics and Bioinformatics
    摘要: The aim of this study was to examine the feasibility of the functional expression of polymorphic OATP1B1s in vivo in the mouse liver. Hydrodynamic gene delivery (HGD) (viz., gene delivery with a rapid intravenous injection of a large volume) with plasmid DNA containing OATP1B1 genes (i.e., wild-type or 521T/C variant form) was used to express corresponding transporters in the mouse liver. Experimental variables (e.g., liver toxicity, optimal delivery vector/the dose of DNA, time required for optimal expression, and effects on endogenous mOatps in the mouse liver) were studied in mice receiving the HGD. Semiquantitative real-time polymerase chain reaction and western blot were carried out to confirm the expression of human OATP1B1 genes in the mouse liver. In vivo transport of pravastatin into the liver was studied in mice expressing wild-type or 521T/C OATP1B1 gene to confirm functional expressions. Alterations in serum biochemistry and hepatocyte histology, created by HGD, were apparently transient and reversible within 3 days of the injection.Gene expression, as determined by the expression of a reporter gene, induced by HGD was found to be liver specific, and pCMV vector showed the highest expression level in the liver. The delivery vector was detected in the plasma, but not in the blood cells, in mice that received HGD, probably due to a transient increase in the permeability of hepatocytes by gene delivery. The optimal DNA dose for delivery was determined to be 50 μg, and the effect of OATP1B1 gene delivery on the endogenous mOatps expressed in the liver was negligible. Under this experimental condition, the expression of OATP1B1 was readily detected in mice receiving injection containing plasmid DNA for the genes. Compared with the control (i.e., the mice expressing wild-type OATP1B1), the uptake was depressed in mice expressing the 521T/C variant, suggesting that this in vivo expression system is functional and capable of discerning the functional difference. In conclusion, in vivo expression of polymorphic human OATP1B1 genes in the mouse liver appeared feasible via HGD, and thus this experimental tool may be useful in the study of pharmacokinetic consequences of polymorphic OATP1B1s in animal models.
    日期: 2011-05
    關聯: Drug Metabolism Reviews. 2011 May;43(Suppl.1):25-26.
    Link to: http://dx.doi.org/10.3109/03602532.2011.567807
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0360-2532&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000289629400048
    顯示於類別:[劉玉麗] 會議論文/會議摘要
    [鄒小蕙] 會議論文/會議摘要
    [林克明(2004-2009)] 會議論文/會議摘要

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