Meta-Analysis of Expression of Hepatic Organic Anion-Transporting Polypeptide (OATP) Transporters in Cellular Systems Relative to Human Liver Tissue
Meta-Analysis of Expression of Hepatic Organic Anion-Transporting Polypeptide (OATP) Transporters in Cellular Systems Relative to Human Liver Tissue
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DOI：
10.1124/dmd.114.062034
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发表时间：
2015-04-01
影响因子：
3.9
通讯作者：
Galetin, Aleksandra
中科院分区：
文献类型：
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作者：
Badee, Justine;Achour, Brahim;Galetin, Aleksandra
有机阴离子转运多肽（OATP）1B 1、OATP 1B 3和OATP 2B 1转运蛋白在肝脏药物处置中发挥重要作用。最近，越来越多的研究报道了OATP转运蛋白的蛋白质组表达数据。然而，缺乏对肝组织和常用细胞系统之间OATP表达的实际差异的系统分析和理解。在本研究中，进行了荟萃分析，以评估肝细胞相对于肝组织中报告的OATP转运蛋白的蛋白表达，并确定同一个体中转运蛋白表达水平的任何潜在相关性。OATP 1B 1被确定为肝组织、三明治培养的人肝细胞（SCHH）和冻存悬浮肝细胞中含量最丰富的摄取转运蛋白，其蛋白质含量分别为5.9 +/- 8.3、5.8 +/- 3.3和4.2 +/- 1.7 fmol/μ g。肝组织和细胞系统中平均表达的等级顺序为OATP 1B 1> OATP 1B 3，接近OATP 2B 1。研究的OATP转运蛋白的异常水平在肝脏和细胞系统之间无显著差异，但SCHH中相对于肝脏组织的OATP 2B 1表达除外。对相同个体（n = 86）的OATP 1B 1、OATP 1B 3和OATP 2B 1肝脏表达数据进行分析，发现存在弱（OATP 1B 1-OATP 2B 1）至中度（OATP 1B 3-OATP 2B 1）显著相关性。OATP 1B 1丰度和人类供体年龄之间存在显著的弱相关性，而研究的OATP表达与性别无关。目前的分析在体外，在体内外推的转运介导的药物处置使用生理基础的药代动力学模型的影响进行了讨论。
Organic anion-transporting polypeptide (OATP)1B1, OATP1B3, and OATP2B1 transporters play an important role in hepatic drug disposition. Recently, an increasing number of studies have reported proteomic expression data for OATP transporters. However, systematic analysis and understanding of the actual differences in OATP expression between liver tissue and commonly used cellular systems is lacking. In the current study, meta-analysis was performed to assess the protein expression of OATP transporters reported in hepatocytes relative to liver tissue and to identify any potential correlations in transporter expression levels in the same individual. OATP1B1 was identified as the most abundant uptake transporter at 5.9 +/- 8.3, 5.8 +/- 3.3, and 4.2 +/- 1.7 fmol/mu g protein in liver tissue, sandwich-cultured human hepatocytes (SCHH), and cryopreserved suspended hepatocytes, respectively. The rank order in average expression in liver tissue and cellular systems was OATP1B1 > OATP1B3 approximate to OATP2B1. Abundance levels of the OATP transporters investigated were not significantly different between liver and cellular systems, with the exception of OATP2B1 expression in SCHH relative to liver tissue. Analysis of OATP1B1, OATP1B3, and OATP2B1 liver expression data in the same individuals (n = 86) identified weak (OATP1B1-OATP2B1) to moderately (OATP1B3-OATP2B1) significant correlations. A significant weak correlation was noted between OATP1B1 abundance and age of human donors, whereas expression of the OATPs investigated was independent of sex. Implications of the current analysis on the in vitro-in vivo extrapolation of transporter-mediated drug disposition using physiologically based pharmacokinetic models are discussed.