Effect of ABCC2 (MRP2) transport function on erythromycin metabolism.
Effect of ABCC2 (MRP2) transport function on erythromycin metabolism.
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DOI：
10.1038/clpt.2011.25
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发表时间：
2011-05
影响因子：
6.7
通讯作者：
Sparreboom A
中科院分区：
文献类型：
--
作者：
Franke RM;Lancaster CS;Peer CJ;Gibson AA;Kosloske AM;Orwick SJ;Mathijssen RH;Figg WD;Baker SD;Sparreboom A
大环内酯类抗生素红霉素具有广泛的肝脏代谢，常被用作检测细胞色素P3A4活性的探针。通过转运蛋白筛选，红霉素被鉴定为转运蛋白ABCC2(MRP2)及其小鼠同源基因Abcc2的底物。由于这些蛋白在肝细胞的胆汁表面高表达，我们推测Abcc2功能受损可能影响肝胆排泄率，从而促进红霉素代谢。利用Abcc2基因敲除的小鼠，我们发现Abcc2缺乏显著增加了红霉素的代谢，而小鼠的CYP3A蛋白表达和微粒体的CYP3A活性并没有受到影响。接下来，在108名人类受试者的队列中，我们观察到ABCC2(Rs717620)中一种常见的功能降低变异的纯合性也与红霉素代谢增加有关，但与咪达唑仑的清除率无关。这些结果表明，ABCC2功能受损可以改变红霉素的代谢，而不依赖于CYP3A4活性的变化。
The macrolide antiobiotic erythromycin undergoes extensive hepatic metabolism and is commonly used as a probe for CYP3A4 activity. Using a transporter screen, erythromycin was identified as a substrate for the transporter ABCC2 (MRP2) and its murine ortholog, Abcc2. Since these proteins are highly expressed on the biliary surface of hepatocytes, we hypothesized that impaired Abcc2 function may influence the rate of hepatobiliary excretion and thereby enhance erythromycin metabolism. Using Abcc2-knockout mice, we found that erythromycin metabolism was significantly increased, whereas murine Cyp3a protein expression and microsomal Cyp3a activity were not affected by Abcc2 deficiency. Next, in a cohort of 108 human subjects, we observed that homozygosity for a common reduced-function variant in ABCC2 (rs717620) was also linked with increased erythromycin metabolism, but was not correlated with the clearance of midazolam. These results suggest that impaired ABCC2 function can alter erythromycin metabolism independently of changes in CYP3A4 activity.