In vitro identification of decreased function phenotype ABCG2 variants

Area of Science:

• Pharmacogenomics
• Molecular Biology
• Drug Metabolism

Background:

• The efflux transporter ABCG2 plays a crucial role in drug absorption and disposition.
• Reduced ABCG2 activity, from inhibition or genetic variants like Q141K, can lead to increased drug plasma levels and variability.
• The functional impact of over 500 rare ABCG2 variants remains largely unknown.

Purpose of the Study:

• To investigate the transport activity and protein abundance of 30 rare, nonsynonymous ABCG2 variants.
• To classify the functional phenotype of these variants relative to the known Q141K variant.
• To assess the potential impact of these variants on drug pharmacokinetics and personalized medicine.

Main Methods:

• Transient expression of 30 rare ABCG2 variants in HEK293 cells.
• Measurement of transport activity and protein abundance using inside-out crude membrane vesicles.
• Normalization of results to reference ABCG2 and categorization based on Q141K variant activity.

Main Results:

• Fourteen rare ABCG2 variants exhibited decreased transport activity compared to the reference.
• Six of these decreased function variants also showed reduced protein abundance.
• Observed changes in transport activity were not fully explained by protein abundance alone.

Conclusions:

• Several rare ABCG2 variants possess a decreased function phenotype, potentially increasing systemic drug exposure.
• These variants may contribute to interindividual variability in drug pharmacokinetics.
• In vitro functional classification of ABCG2 variants can inform personalized drug treatment strategies.