Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations
Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations
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DOI：
10.1128/mcb.23.21.7902-7908.2003
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发表时间：
2003-11-01
影响因子：
5.3
通讯作者：
Schinkel, AH
中科院分区：
文献类型：
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作者：
Jonker, JW;Wagenaar, E;Schinkel, AH
多特异性有机阳离子转运蛋白I和2（Oct 1和-2）转运广泛的底物，包括药物、毒素和内源性化合物。它们在肝、肠（Oct 1）和肾（Oct 1和Oct 2）上皮细胞基底外侧膜中的战略定位表明，它们在从体内清除有毒化合物方面发挥着重要作用。我们先前表明，在Oct 1（-/-）小鼠中，有机阳离子的肝脏摄取和肠道排泄大大减少。由于Oct 1和Oct 2具有广泛重叠的底物特异性，因此它们可能在功能上是冗余的。为了研究这些蛋白质的药理学和生理学作用，我们产生了Oct 2单敲除和Oct 1/2双敲除小鼠。Oct 2（-/-）和Oct 1/2（-/-）小鼠存活且可生育，未显示明显的表型异常。Oct 2本身的缺失对四乙基铵（TEA）的药代动力学几乎没有影响，但在Oct 1/2（-/-）小鼠中，该化合物的肾分泌被完全消除，仅留下肾小球滤过作为TEA清除机制。因此，在Oct 1/2（-/-）小鼠的血浆中TEA的水平显著增加。这项研究表明，Oct 1和Oct 2一起对肾脏分泌（小）有机阳离子至关重要。因此，这些蛋白质的缺乏可能导致药物敏感性和毒性增加。
The polyspecific organic cation transporters I and 2 (Oct1 and -2) transport a broad range of substrates, including drugs, toxins, and endogenous compounds. Their strategic localization in the basolateral membrane of epithelial cells in the liver, intestine (Oct1), and kidney (Oct1 and Oct2) suggests that they play an essential role in removing noxious compounds from the body. We previously showed that in Oct1(-/-) mice, the hepatic uptake and intestinal excretion of organic cations are greatly reduced. Since Oct1 and Oct2 have extensively overlapping substrate specificities, they might be functionally redundant. To investigate the pharmacologic and physiologic roles of these proteins, we generated Oct2 single-knockout and Oct1/2 double-knockout mice. Oct2(-/-) and Oct1/2(-/-) mice are viable and fertile and display no obvious phenotypic abnormalities. Absence of Oct2 in itself had little effect on the pharmacokinetics of tetraethylammonium (TEA), but in Oct1/2(-/-) mice, renal secretion of this compound was completely abolished, leaving only glomerular filtration as a TEA clearance mechanism. As a consequence, levels of TEA were substantially increased in the plasma of Oct1/2(-/-) mice. This study shows that Oct1 and Oct2 together are essential for renal secretion of (small) organic cations. A deficiency in these proteins may thus result in increased drug sensitivity and toxicity.