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Effects of Single Nucleotide Polymorphism Ala270Ser (rs316019) on the Function and Regulation of hOCT2.

Biomolecules. 2019 Oct 07;9(10)
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摘要


The human organic cation transporter 2 (hOCT2) is highly expressed in proximal tubules of the kidneys, where it plays an important role in the secretion of organic cations. Since many drugs are organic cations, hOCT2 has relevant pharmacological implications. The hOCT2 gene is polymorphic, and the nonsynonymous single nucleotide polymorphism (SNP) causing the substitution of alanine at position 270 of the protein sequence with serine (Ala270Ser) is present with high frequency in the human population. Therefore, Ala270Ser has potentially important pharmacologic consequences. Here, we analyzed the transport properties and rapid regulation of hOCT2 wildtype and hOCT2 Ala270Ser expressed in human embryonic kidney cells using real-time uptake measurements. Moreover, we compared the expression of hOCT2 in the plasma membrane determined by biotinylation experiments and the cellular transport and toxicity of cisplatin measured by inductively coupled plasma mass spectrometry and a viability test, respectively. The transport characteristics and regulation of the wildtype and mutated hOCT2 were very similar. Interestingly, a higher affinity of hOCT2 Ala270Ser for creatinine was observed. Compared with hOCT2 wildtype, the plasma membrane expression, cisplatin transport, and cisplatin-associated toxicity of hOCT2 Ala270Ser were significantly lower. In conclusion, these findings suggest that Ala270Ser has subtle but important effects on hOCT2 function, which are probably difficult to detect in studies with patients.

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