Function and Expression of Bile Salt Export Pump in Suspension Human Hepatocytes
Paresh P Chothe1, Rachel Pemberton2, Niresh Hariparsad2
1Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts paresh.chothe@takeda.com.
Drug Metabolism and Disposition: the Biological Fate of Chemicals
|January 21, 2021
Summary
This study confirms bile salt export protein (BSEP) function in suspension human hepatocytes (SHH), crucial for understanding bile salt disposition and drug-induced liver injury. BSEP plays a major role in transporting bile salts in SHH.
Area of Science:
- Hepatology and Drug Metabolism
- Molecular Pharmacology
- Cellular Biology
Background:
- Bile salt disposition mechanisms are not fully understood in suspension human hepatocytes (SHH).
- Limited data exists on bile salt export protein (BSEP) expression and function in SHH.
- Accurate assessment of BSEP function is vital for predicting drug-induced liver injury.
Purpose of the Study:
- To investigate the transport function and expression of BSEP in SHH.
- To characterize BSEP-mediated transport of bile salts using in situ biosynthesis.
- To evaluate the utility of SHH as a model for studying BSEP inhibition.
Main Methods:
- In situ biosynthesis of bile salts (cholic acid [CA] and chenodeoxycholic acid [CDCA]) from precursors in SHH.
- Measurement of conjugated bile salt efflux in a concentration- and time-dependent manner.
- Assessment of BSEP membrane protein abundance and inhibition by known cholestatic agents.
Main Results:
- SHH efficiently generated and transported glycine- and taurine-conjugated CA and CDCA.
- BSEP membrane protein abundance in SHH was comparable to sandwich-cultured human hepatocytes.
- Cholestatic agents significantly inhibited bile salt efflux, with differential effects on G-CA and G-CDCA.
Conclusions:
- BSEP is expressed and functionally active in cryopreserved SHH, playing a major role in bile salt transport.
- SHH serves as a valuable model for mechanistic studies of bile salt disposition.
- This platform can potentially be used for assessing drug-induced BSEP inhibition and liver injury risk.
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