Evaluation of the role of breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated protein 4 (MRP4/ABCC4) in the urinary excretion of sulfate and glucuronide metabolites of edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one)
Evaluation of the role of breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated protein 4 (MRP4/ABCC4) in the urinary excretion of sulfate and glucuronide metabolites of edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one)
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DOI：
10.1124/dmd.107.016352
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发表时间：
2007-11-01
影响因子：
3.9
通讯作者：
Sugiyama, Yuichi
中科院分区：
文献类型：
--
作者：
Mizuno, Naomi;Takahashi, Tsuyoshi;Sugiyama, Yuichi
伊达拉奉(MCI-186；3-甲基-1-苯基-2-吡唑啉-5-酮)是一种自由基清除剂，用于治疗急性脑梗塞。依达拉奉在与葡萄糖醛酸脂或硫酸盐结合后主要排入尿液。先前的研究表明，硫酸依达拉奉是人有机阴离子转运蛋白(OAT)1(SLC22A6)和人OAT3(SLC22A8)的良好底物。在这项研究中，我们研究了乳腺癌耐药蛋白[BCRP(ABCG2)]和[多药耐药相关蛋白4 MRP4(ABCC4)]在肾脏腔外排出中的作用。与对照囊泡(K-m=16.5mM)相比，表达BCRP的膜泡对依达拉奉硫酸依达拉奉摄取增加，但对依达拉奉葡萄糖醛酸摄取无影响。相反，依达拉奉葡萄糖醛酸苷，而不是依达拉奉硫酸盐，在表达MRP4的膜泡中表现出比对照囊泡更大的ATP依赖摄取(K-m=9.85um M)。与牛磺胆酸盐摄取不同，S-甲基谷胱甘肽对MRP4对依达拉奉葡萄糖醛酸苷的摄取没有影响。利用BCRP和MRP4基因敲除小鼠，研究了BCRP和MRP4在硫酸依达拉奉和依达拉奉葡萄糖醛酸尿排泄中的功能重要性。与野生型小鼠相比，BCRP基因敲除小鼠的肾脏对硫酸依达拉奉浓度的清除量显著降低(3.62毫升/分钟/公斤体重)，但并未被完全消除。Mrp4基因敲除小鼠肾组织中依达拉奉葡萄糖醛酸苷的清除量低于野生型小鼠(2.01和5.06 ml/min/kg bw)。我们的结果提示BCRP和MRP4分别参与了伊达拉奉硫酸依达拉奉和伊达拉奉葡萄糖醛酸苷的腔外排出。
Edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is used for the treatment of acute cerebral infarction. Edaravone is mainly excreted into the urine after conjugation to glucuronide or sulfate. Previous studies have demonstrated that edaravone sulfate is a good substrate of human organic anion transporter (OAT) 1 (SLC22A6) and human OAT3 (SLC22A8). In this study, we examined the involvement of breast cancer resistance protein [BCRP (ABCG2)] and [multidrug resistance-associated protein 4 MRP4 (ABCC4)] in the luminal efflux in the kidney. Increased ATP-dependent uptake of edaravone sulfate but not edaravone glucuronide was observed in BCRP-expressing membrane vesicles compared with control vesicles (K-m = 16.5 mu M). In contrast, edaravone glucuronide, but not edaravone sulfate, exhibited greater ATP-dependent uptake in MRP4-expressing membrane vesicles than that in control vesicles (K-m = 9.85 mu M). Unlike taurocholate uptake, S-methylglutathione had no effect on the ATP-dependent uptake of edaravone glucuronide by MRP4. The functional importance of BCRP and MRP4 in the urinary excretion of edaravone sulfate and edaravone glucuronide, respectively, was investigated using Bcrp and Mrp4 knockout mice. The renal clearance with respect to the kidney concentration of edaravone sulfate was reduced significantly but not abolished in Bcrp knockout mice compared with wild-type mice (3.62 versus 4.85 ml/min/kg b.wt.). The renal clearance of edaravone glucuronide was lower in Mrp4 knockout mice than wild-type mice (2.01 versus 5.06 ml/min/kg BW). Our results suggest that Bcrp and Mrp4 are partly involved in the luminal efflux of edaravone sulfate and edaravone glucuronide, respectively.