Tissue distribution and hepatic and renal ontogeny of the multidrug resistance-associated protein (MRP) family in mice
Tissue distribution and hepatic and renal ontogeny of the multidrug resistance-associated protein (MRP) family in mice
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DOI：
10.1124/dmd.105.003780
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发表时间：
2005-07-01
影响因子：
3.9
通讯作者：
Klaassen, CD
中科院分区：
文献类型：
--
作者：
Maher, JM;Slitt, AL;Klaassen, CD
对小鼠基因组的分析揭示了8个多药耐药相关(MRP)转运体，除MRP8外，所有人类MRP的小鼠同源基因。虽然已经检测了MRP在人和大鼠组织中的表达，但没有对小鼠进行表征。此外，小鼠MRPs的个体发育尚不清楚，这些知识可能有助于理解与年龄相关的药代动力学。因此，本研究的目的是定量确定1)MRP家族在12个不同组织中的表达，2)MRP在肝脏和肾脏表达的性别差异，以及3)MRP在发育过程中的表达是否发生变化。MRP家族成员在睾丸、卵巢和胎盘中表达最高，在肠道中表达最高，其次是肝脏和肾脏；在大肠中表达最高；在肾脏中表达最高；在脑中表达最高，其次是肺和胃中；在肝脏中表达最高；在睾丸、肠道和肾脏中表达最高；仅在睾丸中表达。MRP在肾脏中的表达存在性别差异，在肾脏中的表达以MRp1、3和4为主，在肝脏中的表达以女性为主。在肝脏中表达的四种MRP的个体发育过程如下：MRP2和MRP4在出生时在成体水平表达，MRP3在第30天达到成体水平，MRP6在第10天才表达。在肾脏中，MRP1和MRP5在出生时在成体水平表达，而MRP2、3、4和6通常随着时间的推移而增加。综上所述，在不同组织中，不同年龄和性别的个体MRP家族成员的表达存在显著差异。
Analysis of the mouse genome has revealed eight multidrug resistance-associated (Mrp) transporters, with mouse homologs for all human MRPs except MRP8. Whereas MRP expression in tissues of humans and rats has been examined, no characterization exists for mice. Furthermore, the ontogeny of mouse Mrps is unknown, and such knowledge may be helpful in understanding age-related pharmacokinetics. Therefore, the purpose of this study was to quantitatively determine 1) expression of the Mrp family in 12 different tissues, 2) gender variations in Mrp expression in liver and kidney, and 3) whether Mrp expression is altered during development. Highest expression of the Mrp family members is as follows: Mrp1 in testes, ovary, and placenta; Mrp2 in intestine, followed by liver and kidney; Mrp3 in large intestine; Mrp4 in kidney; Mrp5 in brain, followed by lung and stomach; Mrp6 in liver; Mrp7 in testes, intestine, and kidney; and Mrp9 solely in testes. Gender differences in Mrp expression were observed: Mrp1, 3, and 4 in kidney, as well as Mrp1 and 4 in liver were female-predominant. Ontogeny of the four Mrps expressed in liver was as follows: Mrp2 and Mrp4 were expressed at adult levels at birth; Mrp3 reached adult levels at day 30, and Mrp6 was not expressed until day 10. In kidney, Mrp1 and Mrp5 were expressed at adult levels at birth, whereas Mrp2, 3, 4, and 6 generally increased over time. In conclusion, marked differences in expression of the individual Mrp family members exist in various tissues, with age, and with gender.