Trafficking and other regulatory mechanisms for organic anion transporting polypeptides and organic anion transporters that modulate cellular drug and xenobiotic influx and that are dysregulated in disease

Br J Pharmacol. 2017 Jul;174(13):1908-1924. doi: 10.1111/bph.13785. Epub 2017 Apr 24.

Abstract

Organic anion transporters (OATs) and organic anion-transporting polypeptides (OATPs), encoded by a number of solute carrier (SLC)22A and SLC organic anion (SLCO) genes, mediate the absorption and distribution of drugs and other xenobiotics. The regulation of OATs and OATPs is complex, comprising both transcriptional and post-translational mechanisms. Plasma membrane expression is required for cellular substrate influx by OATs/OATPs. Thus, interest in post-translational regulatory processes, including membrane targeting, endocytosis, recycling and degradation of transporter proteins, is increasing because these are critical for plasma membrane expression. After being synthesized, transporters undergo N-glycosylation in the endoplasmic reticulum and Golgi apparatus and are delivered to the plasma membrane by vesicular transport. Their expression at the cell surface is maintained by de novo synthesis and recycling, which occurs after clathrin- and/or caveolin-dependent endocytosis of existing protein. Several studies have shown that phosphorylation by signalling kinases is important for the internalization and recycling processes, although the transporter protein does not appear to be directly phosphorylated. After internalization, transporters that are targeted for degradation undergo ubiquitination, most likely on intracellular loop residues. Epigenetic mechanisms, including methylation of gene regulatory regions and transcription from alternate promoters, are also significant in the regulation of certain SLC22A/SLCO genes. The membrane expression of OATs/OATPs is dysregulated in disease, which affects drug efficacy and detoxification. Several transporters are expressed in the cytoplasmic subcompartment in disease states, which suggests that membrane targeting/internalization/recycling may be impaired. This article focuses on recent developments in OAT and OATP regulation, their dysregulation in disease and the significance for drug therapy.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease*
  • Humans
  • Organic Anion Transporters / metabolism*
  • Peptides / metabolism*
  • Pharmaceutical Preparations*

Substances

  • Organic Anion Transporters
  • Peptides
  • Pharmaceutical Preparations