|Multispecific Drug Transporter Oat3 (Slc22a8) Regulates Multiple Metabolic Pathways.
|Year of Publication
|W. Wu; N. Jamshidi; S.A. Eraly; H.C. Liu; K.T. Bush; B.O. Palsson; S.K. Nigam
|PLoS Comput Biol
|Multispecific drug transporters of the SLC and ABC families are highly conserved through evolution, but their true physiological role remains unclear. Analyses of the organic anion transporter 3 (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 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 and/or signaling pathways. Here we analyzed global gene expression in Oat3 knockout tissue, which implicated Oat3 in Phase I and Phase II metabolism 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., TCA cycle) as well as those involving vitamins (e.g., folate), steroids, prostaglandins, cyclic nucleotides, amino acids, glycans and possibly hyaluronic acid. The data also suggests that Oat3 is essential for the handling of dietary flavonoids and antioxidants.