Hepatocellular Shuttling and Recirculation of Sorafenib-Glucuronide Is Dependent on Abcc2, Abcc3, and Oatp1a/1b.
Hepatocellular Shuttling and Recirculation of Sorafenib-Glucuronide Is Dependent on Abcc2, Abcc3, and Oatp1a/1b.
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DOI：
10.1158/0008-5472.can-15-0280
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发表时间：
2015-07-01
期刊：
影响因子：
11.2
通讯作者：
Schinkel AH
中科院分区：
文献类型：
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作者：
Vasilyeva A;Durmus S;Li L;Wagenaar E;Hu S;Gibson AA;Panetta JC;Mani S;Sparreboom A;Baker SD;Schinkel AH
最近，基于内源性化合物胆红素葡萄糖醛酸脂的研究结果，提出了一种被称为肝细胞跳跃的有效肝脏解毒过程。根据这一模型，肝细胞胆红素葡萄糖醛酸苷可以通过Abcc3转运蛋白介导的外流和随后Oatp1a/1b介导的肝脏摄取遵循肝脏到血液的穿梭循环。我们假设，外源物质的葡醛酸化物结合物，如抗癌药物索拉非尼，也可以经历肝细胞跳跃。利用转运蛋白缺乏的小鼠模型，我们证明了索拉非尼-葡萄糖醛酸苷可以被Abcc2从肝细胞挤出到胆汁中或由Abcc3重新进入体循环，并且它可以被Oatp1a/1b有效地重新摄取到邻近的肝细胞中。我们进一步证明，排入肠腔的索拉非尼-葡萄糖醛酸苷可以被微生物酶裂解成索拉非尼，然后再被吸收，支持其在体循环中的持久性。我们的结果表明，临床药理学中的一个新概念-肝细胞跳跃-肝细胞穿梭过程与进行肝脏葡萄糖醛酸化反应的靶向抗癌药物(如索拉非尼)的解毒具有广泛的相关性。
Recently, an efficient liver detoxification process dubbed ‘hepatocyte hopping’ was proposed based on findings with the endogenous compound, bilirubin glucuronide. According to this model, hepatocytic bilirubin glucuronide can follow a liver-to-blood shuttling loop via Abcc3 transporter-mediated efflux and subsequent Oatp1a/1b-mediated liver uptake. We hypothesized that glucuronide conjugates of xenobiotics, such as the anticancer drug sorafenib, can also undergo hepatocyte hopping. Using transporter-deficient mouse models, we show here that sorafenib-glucuronide can be extruded from hepatocytes into the bile by Abcc2 or back into the systemic circulation by Abcc3, and that it can be taken up efficiently again into neighboring hepatocytes by Oatp1a/1b. We further demonstrate that sorafenib-glucuronide excreted into the gut lumen can be cleaved by microbial enzymes to sorafenib which is then reabsorbed, supporting its persistence in the systemic circulation. Our results suggest broad relevance of a hepatocyte shuttling process known as “hepatocyte hopping” – a novel concept in clinical pharmacology - for detoxification of targeted cancer drugs which undergo hepatic glucuronidation, such as sorafenib.