Post-translational regulation of the major drug transporters in the families of organic anion transporters and organic anion-transporting polypeptides

Abstract

The organic anion transporters (OATs) and organic anion-transporting polypeptides (OATPs) belong to the solute carrier (SLC) transporter superfamily and play important roles in handling various endogenous and exogenous compounds of anionic charge. The OATs and OATPs are often implicated in drug therapy by impacting the pharmacokinetics of clinically important drugs and, thereby, drug exposure in the target organs or cells. Various mechanisms (e.g. genetic, environmental, and disease-related factors, drug-drug interactions, and food-drug interactions) can lead to variations in the expression and activity of the anion drug-transporting proteins of OATs and OATPs, possibly impacting the therapeutic outcomes. Previous investigations mainly focused on the regulation at the transcriptional level and drug-drug interactions as competing substrates or inhibitors. Recently, evidence has accumulated that cellular trafficking, post-translational modification, and degradation mechanisms serve as another important layer for the mechanisms underlying the variations in the OATs and OATPs. This review will provide a brief overview of the major OATs and OATPs implicated in drug therapy and summarize recent progress in our understanding of the post-translational modifications, in particular ubiquitination and degradation pathways of the individual OATs and OATPs implicated in drug therapy.

Keywords: drug transporters; glycosylation; intracellular processing; membrane trafficking; oligomerization; organic anion transporters; organic anion-transporting polypeptides; phosphorylation; protein degradation; protein phosphorylation; transporter; ubiquitylation (ubiquitination).

Figure 1.

Tissue-dependent expression of the major OATs and OATPs implicated in drug therapy. The OATs and OATPs facilitate the directional movement of various endogenous and xenobiotic substrates, including clinically used drugs. Genetic and epigenetic controls coordinate the tissue-dependent expression profiles of these transporters. The OATs and OATPs play important roles in the hepatobiliary transport, renal secretion, intestinal absorption, and blood-brain barrier function by working with the ABC transporters.

Figure 2.

Overview of general cellular processing pathways for the membrane transporters. The central and peripheral quality control (QC) pathways are interconnected and work together, shuffling the transporter proteins inside cells and to the plasma membrane, from the ER and Golgi to various intracellular degradation machinery (e.g. endosomes, lysosomes, proteasomes, aggresomes).

Figure 3.

Schemes showing the published findings on the sites or regions involved in the post-translational regulation of OAT1 (A), OATP1B1 (B), OATP1B3 (C), OATP1A2 (D), and OATP2B1 (E).

Figure 4.

Proposed model based on the published findings of signaling pathways regulating the processing and post-translational regulation of OAT1 (A) and OAT3 (B).