Reactivity of 6-Halopurine Analogs with Glutathione as a Radiotracer for Assessing Function of Multidrug Resistance-Associated Protein 1
Reactivity of 6-Halopurine Analogs with Glutathione as a Radiotracer for Assessing Function of Multidrug Resistance-Associated Protein 1
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DOI：
10.1021/jm901332c
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发表时间：
2009-11-26
影响因子：
7.3
通讯作者：
Irie, Toshiaki
中科院分区：
文献类型：
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作者：
Okamura, Toshimitsu;Kikuchi, Tatsuya;Irie, Toshiaki
据报道，6-溴-7-[C-11]甲基嘌呤通过脑中的谷胱甘肽S-转移酶与谷胱甘肽反应，并转化为多药耐药相关蛋白1（MRP 1）的底物，即外排泵。具有快速转化率的化合物允许定量评估MRP 1功能，但该速率可能易受种间差异的影响。因此，为了应用于不同的物种，包括人类，有必要通过改变化学结构来调节转化率。因此，我们设计了6-卤代-9-（或7）-[C-14]甲基嘌呤（卤素：F、Cl、Br或I），并使用小鼠、大鼠或猴的脑匀浆在体外评价了它们与谷胱甘肽的酶反应性。这些物种之间的反应性存在显著差异。N-甲基-6-卤代嘌呤上甲基和卤素位置的变化提供了与谷胱甘肽具有广泛反应性的各种化合物。总之，调整6-溴-7-[C-11]甲基嘌呤的反应性可以评估各种物种大脑中的MRP 1功能。
6-Bromo-7-[C-11]methylpurine is reported to react with glutathione via glutathione S-transferases in the brain and to be converted into a substrate for multidrug resistance-associated protein 1 (MRP1), an efflux pump. The compound with a rapid conversion rate allows quantitative assessment of MRP1 function, but this rate is probably susceptible to interspecies differences. Hence, for application to different species, including humans, it is necessary to adjust the conversion rate by modifying the chemical structure. We therefore designed 6-Halo-9-(or 7)-[C-14]methylpurine (halogen: F, Cl, Br, or I), and evaluated them in vitro with respect to enzymatic reactivity with glutathione using brain homogenates from the mouse, rat, or monkey. There was a marked difference in reactivity between these species. Changes in the position of the methyl group and halogen on N-methyl-6-halopurine provided various compounds possessing wide-ranging reactivity with glutathione. In conclusion, the adjustment of reactivity of 6-bromo-7-[C-11]methylpurine may allow assessment of MRP1 function in the brain in various species.