In vitro characterization of SLCO2B1 genetic variants

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Alli Sinokki1, Annika Miinalainen1, Saara Kivioja1

  • 1Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki FI-00014, Finland.

Journal of Pharmaceutical Sciences
|March 28, 2025
PubMed

Insights

Genetic variations in the OATP2B1 transporter (encoded by SLCO2B1) can affect drug metabolism. The rare variant c.1559G>C significantly impairs OATP2B1 function, impacting drug disposition.

Area of Science:

  • Pharmacogenomics
  • Drug Transporter Functionality

Background:

  • OATP2B1 (encoded by SLCO2B1) is a crucial drug transporter in the intestine and liver.
  • Genetic variations in SLCO2B1 can alter the disposition of OATP2B1 substrate drugs.
  • The functional impact of rare OATP2B1 variants is not well understood.

Purpose of the Study:

  • To characterize the in vitro functionality of naturally occurring missense single nucleotide variants of SLCO2B1.
  • To assess the impact of specific SLCO2B1 variants (c.601G>A, c.935G>A, c.953C>T, c.1175C>, c.1457C>T, c.1559G>C, c.1596C>A, and c.601G>A + c.935G>A haplotype) on OATP2B1 transporter activity.

Main Methods:

  • HEK293 cells expressing OATP2B1 reference and variant forms were used.
  • Cellular uptake of OATP2B1 substrates (dibromofluorescein, 5-carboxyfluorescein, estrone sulfate, rosuvastatin) was measured.
  • OATP2B1 variant protein abundance was quantified using LC-MS/MS-based quantitative targeted absolute proteomics.

Main Results:

  • The SLCO2B1 variant c.1559G>C almost completely impaired OATP2B1-mediated uptake of all tested substrates.
  • Protein abundance of the c.1559G>C variant was reduced, but not proportionally to the loss of function.
  • Other studied SLCO2B1 variants showed comparable or modestly reduced protein abundance and transport function.

Conclusions:

  • The c.1559G>C variant represents a significant loss-of-function variant for OATP2B1.
  • These findings aid in interpreting clinical pharmacogenetic studies involving SLCO2B1 variants.
  • The characterization of rare variants like c.1559G>C is crucial for predicting drug response and potential adverse events.
Keywords:
Drug transportGenetic polymorphism(s)Hepatic transportIntestinal transporter(s)Membrane transporter(s)Organic Anion-Transporting Polypeptide(s) (OATP)PharmacogeneticsSingle nucleotide polymorphism (SNP)Solute Carrier (SLC) transporter(s)

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