Thyroid hormone export from cells: contribution of P-glycoprotein

Area of Science:

• Cell Biology
• Endocrinology
• Molecular Biology

Background:

• Tri-iodothyronine (T3) transport across cell membranes is crucial for its biological activity.
• Multidrug resistance-associated (MDR) proteins, including P-glycoprotein (P-gp), are implicated in the transport of various molecules.
• The specific role of P-gp in thyroid hormone efflux has not been directly investigated.

Purpose of the Study:

• To investigate the direct involvement of P-glycoprotein (P-gp) in the cellular efflux of tri-iodothyronine (T3).
• To compare T3 transport in cells with and without P-gp overexpression.
• To assess the effect of MDR inhibitors on T3 efflux.

Main Methods:

• Utilized MDCKII cells transfected with mdr1 cDNA (MDCKII-MDR) and wild-type MDCKII cells.
• Measured 125I-T3 efflux rates using radiolabeled T3.
• Confirmed P-gp expression via Western blotting.
• Examined the effects of verapamil, nitrendipine, VX 853, and VX 710 on T3 efflux.

Main Results:

• MDCKII-MDR cells exhibited a twofold higher rate of 125I-T3 efflux compared to wild-type MDCKII cells.
• Cellular accumulation of 125I-T3 was reduced in MDCKII-MDR cells, suggesting enhanced export.
• Specific MDR inhibitors (VX 853 and VX 710) significantly reduced 125I-T3 efflux in MDCKII-MDR cells, but not in wild-type cells.

Conclusions:

• Provided the first direct evidence that P-glycoprotein (P-gp) actively exports thyroid hormone (T3) from cells.
• Verapamil and nitrendipine likely inhibit other cellular T3 transporters in addition to P-gp.
• P-gp plays a significant role in regulating intracellular thyroid hormone levels through direct efflux.