Departments of Pediatrics (H.C.L., K.T.B., S.K.N.), Medicine, Division of Nephrology and Hypertension (W.W., S.A.E., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Bioengineering (N.J., B.O.P., S.K.N.), University of California, San Diego, La Jolla, California.
Drug Metab Dispos. 2013 Oct;41(10):1825-34. doi: 10.1124/dmd.113.052647. Epub 2013 Aug 6.
Multispecific drug transporters of the solute carrier and ATP-binding cassette families are highly conserved through evolution, but their true physiologic role remains unclear. Analyses of the organic anion transporter 3 (OAT3; encoded by Slc22a8/Oat3, originally Roct) knockout mouse have confirmed its critical role in the renal handling of common drugs (e.g., antibiotics, antivirals, diuretics) and toxins. Previous targeted metabolomics of the knockout of the closely related Oat1 have demonstrated a central metabolic role, but the same approach with Oat3 failed to reveal a similar set of endogenous substrates. Nevertheless, the Oat3 knockout is the only Oat described so far with a physiologically significant phenotype, suggesting the disturbance of metabolic or signaling pathways. Here we analyzed global gene expression in Oat3 knockout tissue, which implicated OAT3 in phase I and phase II metabolism (drug metabolizing enzymes or DMEs), as well as signaling pathways. Metabolic reconstruction with the recently developed "mouse Recon1" supported the involvement of Oat3 in the aforementioned pathways. Untargeted metabolomics were used to determine whether the predicted metabolic alterations could be confirmed. Many significant changes were observed; several metabolites were tested for direct interaction with mOAT3, whereas others were supported by published data. Oat3 thus appears critical for the handling of phase I (hydroxylation) and phase II (glucuronidation) metabolites. Oat3 also plays a role in bioenergetic pathways (e.g., the tricarboxylic acid cycle), as well as those involving vitamins (e.g., folate), steroids, prostaglandins, gut microbiome products, uremic toxins, cyclic nucleotides, amino acids, glycans, and possibly hyaluronic acid. The data seemingly consistent with the Remote Sensing and Signaling Hypothesis (Ahn and Nigam, 2009; Wu et al., 2011), also suggests that Oat3 is essential for the handling of dietary flavonoids and antioxidants.
多特异性药物转运蛋白属于溶质载体和 ATP 结合盒家族，在进化过程中高度保守，但它们的确切生理功能仍不清楚。有机阴离子转运蛋白 3（OAT3；由 Slc22a8/Oat3 编码，最初称为 Roct）敲除小鼠的分析证实了其在肾脏处理常见药物（如抗生素、抗病毒药、利尿剂）和毒素中的关键作用。先前对密切相关的 Oat1 敲除的靶向代谢组学研究表明其具有重要的中心代谢作用，但对 Oat3 采用相同方法却未能揭示出一组类似的内源性底物。然而，到目前为止，Oat3 是唯一具有生理意义表型的 Oat，这表明其代谢或信号通路受到干扰。在这里，我们分析了 Oat3 敲除组织中的全基因表达，这表明 OAT3 参与了 I 相和 II 相代谢（药物代谢酶或 DMEs）以及信号通路。最近开发的“mouse Recon1”进行的代谢重建支持 Oat3 参与上述途径。非靶向代谢组学用于确定是否可以证实预测的代谢变化。观察到许多显著变化；对几种代谢物进行了直接与 mOAT3 相互作用的测试，而其他代谢物则得到了已发表数据的支持。因此，Oat3 似乎对 I 相（羟化）和 II 相（葡萄糖醛酸化）代谢物的处理至关重要。Oat3 还在能量代谢途径（如三羧酸循环）以及涉及维生素（如叶酸）、类固醇、前列腺素、肠道微生物组产物、尿毒症毒素、环核苷酸、氨基酸、聚糖和可能的透明质酸的途径中发挥作用。这些数据似乎与远程传感和信号假说（Ahn 和 Nigam，2009；Wu 等人，2011）一致，也表明 Oat3 对于处理膳食类黄酮和抗氧化剂是必需的。
