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Review
. 2021 Jan:217:107647.
doi: 10.1016/j.pharmthera.2020.107647. Epub 2020 Aug 3.

Regulation of organic anion transporters: Role in physiology, pathophysiology, and drug elimination

Jinghui Zhang  1 , Haoxun Wang  1 , Yunzhou Fan  1 , Zhou Yu  1 , Guofeng You  2
Affiliations
Review

Regulation of organic anion transporters: Role in physiology, pathophysiology, and drug elimination

Jinghui Zhang et al. Pharmacol Ther. 2021 Jan.

Abstract

The members of the organic anion transporter (OAT) family are mainly expressed in kidney, liver, placenta, intestine, and brain. These transporters play important roles in the disposition of clinical drugs, pesticides, signaling molecules, heavy metal conjugates, components of phytomedicines, and toxins, and therefore critical for maintaining systemic homeostasis. Alterations in the expression and function of OATs contribute to the intra- and inter-individual variability of the therapeutic efficacy and the toxicity of many drugs, and to many pathophysiological conditions. Consequently, the activity of these transporters must be highly regulated to carry out their normal functions. This review will present an update on the recent advance in understanding the cellular and molecular mechanisms underlying the regulation of renal OATs, emphasizing on the post-translational modification (PTM), the crosstalk among these PTMs, and the remote sensing and signaling network of OATs. Such knowledge will provide significant insights into the roles of these transporters in health and disease.

Keywords: Drug disposition; Drug transporter; Organic anion transporter; Post-translational modification; Regulation.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that there are no conflicts of interest.

Figures

Fig. 1.
Fig. 1.
Major drug transporters expressed in human renal proximal tubule cells. MRP: multidrug resistance-associated protein, OCT: organic cation transporter, OAT: organic anion transporter, OATP: organic anion-transporting peptide, MATE: multidrug and toxin extrusion protein, PEPT: peptide transporter, BCRP: breast cancer resistance protein, MDR: multidrug resistance mutation, URAT: urate transporter.
Fig. 2.
Fig. 2.
Phosphorylation of Ubiquitin ligase Nedd4-2 mediates the regulation of OAT transport activity by various kinases. U: ubiquitin, P: Phosphoryl group, S: Serine, T: Threonine, PKC: Protein kinase C, Sgk1/2: Serum- and glucocorticoid-inducible kinase 1/2, Nedd4-2: Neural precursor cell expressed developmentally down-regulated 4-2.
Fig. 3.
Fig. 3.
Regulation of OATs by Ubiquitination, deubiquiting enzyme USP8, and proteasome inhibitors. U: ubiquitin, USP8: ubiquitin-specific proteases 8, Nedd4-1/Nedd4-2: Neural precursor cell expressed developmentally down-regulated 4-1/4-2.
Fig. 4.
Fig. 4.
Regulation of OATs by SUMOylation and deSUMOylation enzyme Senp2. S: SUMO, Senp2: SUMO1/sentrin specific peptidase 2, PKA: Protein kinase A.
See this image and copyright information in PMC

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