Interspecies Variability in Expression of Hepatobiliary Transporters across Human, Dog, Monkey, and Rat as Determined by Quantitative Proteomics
Interspecies Variability in Expression of Hepatobiliary Transporters across Human, Dog, Monkey, and Rat as Determined by Quantitative Proteomics
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DOI：
10.1124/dmd.114.061580
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发表时间：
2015-03-01
影响因子：
3.9
通讯作者：
Unadkat, Jashvant D.
中科院分区：
文献类型：
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作者：
Wang, Li;Prasad, Bhagwat;Unadkat, Jashvant D.
我们用液相色谱-质谱法对55例人肝库中BSEP、MATE1、MRP3、MRP4、NTCP和OCT1转运蛋白的表达进行了定量，并确定了蛋白表达与性别、年龄和基因的关系。这些数据补充了我们之前在同一家肝脏银行所做的工作，在那里我们量化了OATPs、BCRP、MDR1和MRP2的蛋白表达。此外，我们量化和比较了与上述人类转运蛋白相对应的肝胆转运蛋白在雄性比格犬、食蟹猴、SpragueDawley大鼠和Wistar大鼠肝组织和肝细胞中的表达差异。在所有物种中，正弦OATPs/OATPs是最丰富的肝脏转运蛋白。然而，其余转运蛋白的相对丰度在物种间存在显著差异。例如，在人类和猴子中第二丰富的转运蛋白是OCT1/Oct1，而在狗/Wistar大鼠和Spraogue-Dawley大鼠中分别是MRP2和Ntcp。相比之下，外排转运蛋白BCRP/BCRP、MDR1/MDR1、MRP3/MRP3、MRP4/MRP4和MATE1/Mate1在所有物种中的蛋白表达都要低得多。对于大多数转运蛋白，在肝组织中的表达与未经电镀的冷冻保存的肝细胞中的表达相当。这些关于人类肝脏转运蛋白表达的数据完整地描绘了在药物处置和毒性中重要的主要人类肝胆转运蛋白的表达情况。此外，相应的肝胆转运蛋白在临床前物种中的表达数据将有助于解释和推断临床前研究对人类的药代动力学、药理学和毒理学结果。
We quantified, by liquid chromatography tandemmass spectrometry, transporter protein expression of BSEP, MATE1, MRP3, MRP4, NTCP, and OCT1 in our human liver bank (n = 55) and determined the relationship between protein expression and sex, age and genotype. These data complement our previous work in the same liver bank where we quantified the protein expression of OATPs, BCRP, MDR1, and MRP2. In addition, we quantified and compared the interspecies differences in expression of the hepatobiliary transporters, corresponding to the above human transporters, in liver tissue and hepatocytes of male beagle dogs, cynomolgus monkeys, SpragueDawley rats, and Wistar rats. In all the species, the sinusoidal OATPs/Oatps were the most abundant hepatic transporters. However, there were notable interspecies differences in the relative abundance of the remaining transporters. For example, the next most abundant transporter in humans and monkeys was OCT1/Oct1, whereas it was Mrp2 and Ntcp in dogs/Wistar rats and Sprague-Dawley rats, respectively. In contrast, the protein expression of the efflux transporters BCRP/Bcrp, MDR1/Mdr1, MRP3/Mrp3, MRP4/Mrp4, and MATE1/Mate1 was much lower across all the species. For most transporters, the expression in the liver tissues was comparable to that in the unplated cryopreserved hepatocytes. These data on human liver transporter protein expression complete the picture of the expression of major human hepatobiliary transporters important in drug disposition and toxicity. In addition, the data on expression of the corresponding hepatobiliary transporters in preclinical species will be helpful in interpreting and extrapolating pharmacokinetic, pharmacological, and toxicological results from preclinical studies to humans.