Visualization of Hepatic Uptake Transporter Function in Healthy Subjects by Using Gadoxetic Acid-enhanced MR Imaging
Visualization of Hepatic Uptake Transporter Function in Healthy Subjects by Using Gadoxetic Acid-enhanced MR Imaging
复制标题
DOI：
10.1148/radiol.12112061
复制
发表时间：
2012-09-01
期刊：
影响因子：
19.7
通讯作者：
Kuehn, Jens-Peter
中科院分区：
文献类型：
--
作者：
Nassif, Ali;Jia, Jia;Kuehn, Jens-Peter
目的：为了确定是否肝特异性的人有机阴离子转运多肽（OATP）1B 1和OATP 1B 3的遗传多态性的影响细胞摄取钆塞酸在体外，如果功能相关的多态性的混杂因素，肝增强钆塞酸在健康subjects.Materials和方法：本研究获得伦理批准，所有的科目提供书面知情同意书。使用稳定转染的胚肾HEK 293细胞测量了OATP 1B 1和OATP 1B 3及其常见遗传变体对钆乙酸的细胞摄取。在36名SLCO 1B 1/1B 3野生型等位基因（n = 10）、SLCO 1B 1 *1b/*1b（n = 8）、SLCO 1B 1 *15/*15（n = 7）、SLCO 1B 1 *5/* 15（n = 1）、SLCO 1B 1 *1a/*5（n = 6）、和SLCO 1B 3 *4/*4（n = 4）的T1加权磁共振成像和液相色谱串联质谱。在用SLCO 1B 1c转染的细胞中，钆塞酸的转运活性增加。388 A>G（12.8 pmol/[mg.min] +/- 3.53，P = .001），但在SLCO 1B 1c细胞中降低。388 A>G/521 T>C（3.11 pmol/[mg.min] +/- 0.918，P = 0.004）与具有非变异转运蛋白的细胞（6.32 pmol/[mg.min] +/- 2.73）相比。与用非变异SLCO 1B 3转染的细胞的活性相比，（7.43 pmol/[mg.min] +/- 2.43），SLCO1B3c.699G>A是功能获得性变体（15.1 pmol/[mg.min] +/- 5.52，P = .002），而SLCO1B3c.334T>G（0.364 pmol/[mg.min] +/- 0.125，P = .0001）和SLCO1B3c.1564G>T（0.295 pmol/[mg.min] +/- 0.247，P = .0001）是功能较低的变异体。与野生型受试者和OATP 1B 1 * 1b/*1b受试者相比，OATP 1B 1 *1a/*5受试者中钆塞酸的肝脏增强作用降低（增强曲线下面积，3-480分钟，任意单位[Au]; 20.7 Au +/- 6.85 vs 36.5 Au +/- 8.08 [P = .006] vs 34.6 Au +/- 8.92 [P = .026]）。OATP 1B 3 *4多态性与功能无关。结论：肝脏特异性OATP 1B 1和OATP 1B 3基因多态性是钆塞酸在人体内的吸收载体。OATP 1B 1基因多态性是钆塞酸增强肝脏MR成像的信号混杂因素。(C)RSNA，2012年
Purpose: To determine if genetic polymorphisms of liver-specific human organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 influence cellular uptake of gadoxetic acid in vitro and if functionally relevant polymorphisms are confounders for liver enhancement by gadoxetic acid in healthy subjects.Materials and Methods: This study received ethics approval, and all subjects provided written informed consent. Cellular uptake of gadoxetic acid by OATP1B1 and OATP1B3 and their frequent genetic variants was measured by using stable transfected embryonic kidney HEK293 cells. Liver signal intensity at gadoxetic acid-enhanced MR imaging and pharmacokinetics of gadoxetic acid were evaluated in 36 healthy carriers of SLCO1B1/1B3 wild-type alleles (n = 10), SLCO1B1*1b/*1b (n = 8), SLCO1B1*15/*15 (n = 7), SLCO1B1*5/*15 (n = 1), SLCO1B1*1a/*5 (n = 6), and SLCO1B3*4/*4 (n = 4) by using T1-weighted MR imaging and liquid chromatography tandem mass spectrometry.Results: Transport activity for gadoxetic acid was increased in cells transfected with SLCO1B1c.388A>G (12.8 pmol/[mg.min] +/- 3.53, P = .001) but decreased in cells with SLCO1B1c.388A>G/521T>C (3.11 pmol/[mg.min] +/- 0.918, P = .004) compared with cells with nonvariant transporter (6.32 pmol/[mg.min] +/- 2.73). Compared with activity of cells transfected with the nonvariant SLCO1B3 (7.43 pmol/[mg.min] +/- 2.43), SLCO1B3c.699G>A was a gain-of-function variant (15.1 pmol/[mg.min] +/- 5.52, P = .002), whereas SLCO1B3c.334T>G (0.364 pmol/[mg.min] +/- 0.125, P = .0001) and SLCO1B3c.1564G>T (0.295 pmol/[mg.min] +/- 0.247, P = .0001) were variants with lower function. Liver enhancement with gadoxetic acid was reduced in subjects with OATP1B1*1a/*5 compared with wild-type subjects and those with OATP1B1*1b/*1b (area under enhancement curve, 3-480 minutes in arbitrary units [au]; 20.7 au +/- 6.85 vs 36.5 au +/- 8.08 [P = .006] vs 34.6 au +/- 8.92 [P = .026]). The OATP1B3*4 polymorphism was not of functional relevance. No pharmacokinetic characteristics of gadoxetic acid were influenced by genetic polymorphisms of OATP1B1 and OATP1B3.Conclusion: Liver-specific OATP1B1 and OATP1B3 are uptake carriers for gadoxetic acid in subjects. Genetic polymorphisms of OATP1B1 are signal confounders in gadoxetic acid-enhanced liver MR imaging. (C) RSNA, 2012