Divergent Regulation of OCT and MATE Drug Transporters by Cadmium Exposure

Hong Yang,Shiwei Zhou,Yan Shu,Qing Li,Dong Guo,Obinna N Obianom

doi:10.3390/pharmaceutics13040537

Abstract

Coordinated transcellular transport by the uptake via organic cation transporters (OCTs) in concert with the efflux via multidrug and toxin extrusion proteins (MATEs) is an essential system for hepatic and renal drug disposition. Despite their clinical importance, the regulation of OCTs and MATEs remains poorly characterized. It has been reported that cadmium (Cd2+) increase the activities of OCTs while being a substrate of MATEs. Here, we found that human (h) OCT2 protein, as compared with hMATE1, was more active in trafficking between the plasma membrane and cytoplasmic storage pool. Cd2+ exposure could significantly enhance the translocation of hOCT2 and hOCT1, but not hMATE1, to the plasma membrane. We further identified that candesartan, a widely prescribed angiotensin II receptor blocker, behaved similarly toward OCT2 and MATE1 as Cd2+ did. Importantly, Cd2+ and candesartan treatments could lead to an enhanced accumulation of metformin, which is a well-characterized substrate of OCTs/MATEs, in mouse kidney and liver, respectively. Altogether, our studies have uncovered possible divergent regulation of OCTs and MATEs by certain xenobiotics, such as Cd2+ and candesartan due to the different cellular trafficking of these two families of transporter proteins, which might significantly affect drug disposition in the liver and kidney.

Highlights

The human genome encodes more than 400 membrane transporters that function as gatekeepers in determining the selective permeability of the cell membrane [1]
The understanding of regulation of organic cation transporters (OCTs)/multidrug and toxin extrusion proteins (MATEs) remains lagged far behind the extensive research demonstrating the critical role of these transporters in drug disposition
We have shown that hOCT2 protein, not hMATE1, was actively trafficking between plasma membrane and cytoplasmic storage pool, which was subject to the regulation by Cd2+ exposure

Summary

Introduction

The human genome encodes more than 400 membrane transporters that function as gatekeepers in determining the selective permeability of the cell membrane [1]. The hepatocytes and the proximal tubular cells in the renal cortex are highly equipped with a variety of membrane transporters that are essential for hepatic and tubular uptake and the secretion of numerous endogenous and exogenous chemicals, including therapeutic drugs [2,3]. MATEs) are pairs of the solute carrier (SLC) transporter families highly expressed in the basolateral and apical membrane of hepatocytes (OCT1 and MATE1 in human and mouse) and renal proximal tubular cells (OCT2 and MATE1/2-K in human, OCT1/2 and MATE1 in mouse), respectively [6]. Due to the large overlap in their substrates, OCTs and MATEs often function in tandem to vectorially transport chemicals from blood into bile or urine.

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Conclusion