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Characterization of Membrane Transporters by Heterologous Expression in E. coli and Production of Membrane Vesicles
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Colistin is substrate of the carnitine/organic cation transporter 2 (OCTN2, SLC22A5)

Michele Visentin1, Zhibo Gai2, Angelo Torozi2

  • 1Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland michele.visentin@usz.ch.

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|October 8, 2017
PubMed

Insights

Colistin causes kidney damage due to accumulation in renal cells. The carnitine/organic cation transporter 2 (OCTN2) mediates colistin uptake, and blocking this transporter protects against colistin toxicity.

Area of Science:

  • Pharmacology
  • Nephrology
  • Molecular Biology

Background:

  • Colistin is vital for treating multidrug-resistant gram-negative infections.
  • Nephrotoxicity limits colistin's clinical use, possibly due to renal cortex accumulation.
  • The renal transport mechanisms for colistin remain poorly understood.

Purpose of the Study:

  • To investigate the specific membrane transporters responsible for colistin's renal handling.
  • To elucidate the mechanism of colistin accumulation in the kidney.

Main Methods:

  • Utilized HEK293 cells stably expressing key proximal tubule apical membrane transporters.
  • Assayed [14C]colistin transport in cells expressing OCTN2, OCT1, and OCTN1.
  • Investigated interactions between colistin, L-carnitine, and tetraethylammonium bromide (TEA) transport via OCTN2.
  • Examined colistin uptake in primary mouse proximal tubular cells with and without OCTN2 inhibition.

Main Results:

  • [14C]Colistin was significantly transported by OCTN2 (SLC22A5), but not by OCT1 or OCTN1.
  • Colistin competitively inhibited [14C]TEA transport and non-competitively inhibited [3H]L-carnitine transport via OCTN2.
  • OCTN2-mediated [14C]colistin uptake was independent of sodium (Na+).
  • Inhibition of OCTN2-mediated colistin transport with L-carnitine protected primary mouse proximal tubular cells from colistin-induced toxicity.

Conclusions:

  • The carnitine/organic cation transporter 2 (OCTN2) is a key transporter involved in renal colistin handling.
  • Colistin-induced nephrotoxicity is likely mediated by its intracellular accumulation via OCTN2.
  • Targeting OCTN2-mediated transport may offer a strategy to mitigate colistin nephrotoxicity.

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