Multidrug Resistance-Associated Proteins 3 and 5 Play a Role in the Hepatic Transport of Mercuric Conjugates of Glutathione

TL;DR

This study shows that MRP3 and MRP5 transport mercury conjugated with glutathione in liver cells.

Contribution

The study is the first to demonstrate that MRP3 and MRP5 can export mercury conjugates.

Findings

GSH-Hg-GSH is a substrate for MRP3 and MRP5 transporters.

Transport of GSH-Hg-GSH by MRP3 and MRP5 follows saturable kinetics.

This is the first evidence that MRP3 and MRP5 can export mercury.

Abstract

Multidrug resistance proteins (MRPs) are transporters for metabolic waste and xenobiotics and are known to export a wide range of substances from renal tubular cells. This study aimed to define and characterize the transport of mercuric conjugates of glutathione (GSH-Hg-GSH) in inside-out membrane vesicles containing MRP3 and MPR5. The functionality of the MRP3 and MRP5 vesicles was confirmed by measuring the uptake of [3H]-estradiol and 5-6-carboxy-2′,7′-dichloro-fluorescein (CDCF) over time (at 1, 5, 15, and 30 min). The uptake of GSH-Hg-GSH, containing radioactive mercury ([203Hg]), was measured in each set of membrane vesicles over time, and the findings suggest that GSH-Hg-GSH is a substrate of MRP3 and MRP5. The saturation kinetics were also analyzed by measuring the uptake of 10 µM GSH-[203Hg]-GSH in the presence of 25, 50, or 100 µM unlabeled GSH-Hg-GSH for 5 min at 37 °C. The transport of GSH-Hg-GSH by MRP3 (Vmax = 25.6 µM; Km = 2.8 µM) and MRP5 (Vmax = 32.9 µM; Km = 4.9 µM) was saturable. These findings are the first to show that MRP3 and MRP5 are capable of mediating the export of any form of mercury.

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