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Published on: April 4, 2018
In vitro characterization of SLCO2B1 genetic variants
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
Summary
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.
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