Regulation of OATP1B1 Function by Tyrosine Kinase-mediated Phosphorylation
OATP1B1 (SLCO1B1) is the most abundant and pharmacologically relevant uptake transporter in the liver and a key mediator of xenobiotic clearance. However, the regulatory mechanisms that determine OATP1B1 activity remain uncertain, and as a result, unexpected drug-drug interactions involving OATP1B1...
Saved in:
Published in | Clinical cancer research Vol. 27; no. 15; pp. 4301 - 4310 |
---|---|
Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.08.2021
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | OATP1B1 (SLCO1B1) is the most abundant and pharmacologically relevant uptake transporter in the liver and a key mediator of xenobiotic clearance. However, the regulatory mechanisms that determine OATP1B1 activity remain uncertain, and as a result, unexpected drug-drug interactions involving OATP1B1 substrates continue to be reported, including several involving tyrosine kinase inhibitors (TKI).
OATP1B1-mediated activity in overexpressing HEK293 cells and hepatocytes was assessed in the presence of FDA-approved TKIs, while rosuvastatin pharmacokinetics in the presence of an OATP1B1 inhibiting TKI were measured
. Tyrosine phosphorylation of OATP1B1 was determined by LC/MS-MS-based proteomics and transport function was measured following exposure to siRNAs targeting 779 different kinases.
Twenty-nine of 46 FDA-approved TKIs studied significantly inhibit OATP1B1 function. Inhibition of OATP1B1 by TKIs, such as nilotinib, is predominantly noncompetitive, can increase systemic concentrations of rosuvastatin
, and is associated with reduced phosphorylation of OATP1B1 at tyrosine residue 645. Using genetic screens and functional validation studies, the Src kinase LYN was identified as a potential regulator of OATP1B1 activity that is highly sensitive to inhibition by various TKIs at clinically relevant concentrations.
A novel kinase-dependent posttranslational mechanism of OATP1B1 activation was identified and interference with this process by TKIs can influence the elimination of a broad range of xenobiotic substrates. |
---|---|
Bibliography: | Performed research- S.H., E.H., M.Q., K.P., S.S, S.S.O., T.C., A.G., J.P., Y.J., M.E.U. Wrote the paper- S.H., E.H., J.A.S. Data analysis and interpretation- S.H, E.H., K.H, A.P. Contributed reagents or analytical tools- J.Q. Critical revisions- A.S., S.H., J.A.S. Author Contributions Study conception and design- J.A.S., S.H., A.S., J.Q. |
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-21-0023 |