Effect of Cadmium Exposure on the Transport System of Organic Cation Transporters and Multidrug and Toxin Extrusion Proteins (OCTs/MATEs)

Abstract

The universal pollution by cadmium (Cd) in our agricultural land and the prevalence of cigarette smoking make the environmental Cd exposure an unneglectable human health concern. While the mechanism of cadmium accumulation has been extensively studied, no explicit mechanism has been reported regarding the elimination of cadmium from the body. On the other hand, whereas Cd exposure has been correlated with a variety of diseases, little is known pertaining to its effect on drug disposition and response in patients. Thus, we aim to delineate the mechanism of cadmium elimination and detoxification and to gain new insights into its effect on xenobiotic disposition and response.

The OCTs/MATEs transport system are pair of transporter proteins highly expressed at the basolateral and apical membrane of hepatocytes and renal proximal tubules respectively. Recently, Cd has been identified as a substrate of OCTs, while we determined that MATEs could reduce the toxicity of Cd by serving as its efflux transporters in vitro. In addition, knockout of Mate1 in mice kidney resulted in higher renal toxicity in both chronic and acute Cd intoxication studies. We found that Cd was an inducer of OCT activity while an inhibitor towards MATEs in cells. Consistently, Cd exposure could lead to accumulation of the substrates of these transporters in mouse liver and kidney. Being focused on human (h) OCT2 and MATE1, our mechanistic studies revealed that hOCT2, as compared to hMATE1, was more active in trafficking between the plasma membrane and the cytoplasmic storage pool. Cd exposure could trigger the formation of a protein complex consisting of AKT2, calmodulin and AS160, which could then selectively facilitate the phosphorylation of AKT2 at T309, and initiate the translocation of hOCT2 to the plasma membrane.

Altogether, our findings have identified MATE transporters as new contributors for Cd detoxification, and provided foundation to uncover environmental Cd as a previously unrecognized factor for the broad variation in drug disposition and response.