Impact of Cadmium Exposure on Transporter Function and Drug Disposition in the Kidney

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PROJECT SUMMARY/ABSTRACT The heavy metal cadmium (Cd) is currently ranked 7th on the 2019 US Agency for Toxic Substances and Disease Registry (ATSDR) and listed as one of Priority Pollutants by US Environmental Protection Agency (EPA). Although intoxication by high levels of Cd exposure is rarely seen nowadays, chronic low levels of Cd exposure is still a major health concern as Cd is a cumulative metal with an extremely long biological half-life of 10-30 years in human body. Cd exposure has been associated with increased incidence of multiple diseases. Strikingly, little is known whether chronic Cd exposure would affect the disposition of drugs that are used to treat diseases. Renal transporter proteins involve in drug disposition by mediating drug transport across tubular cells and particularly proximal tubules. Coordinated transcellular transport by uptake transporters, such as organic cation transporters (OCTs) and organic anion transporters (OATs) in the basolateral membrane in concert with efflux transporters, such as multidrug and toxin extrusion proteins (MATEs) and multidrug resistance-associated proteins (MRPs) in the apical membrane of tubular cells, is believed to be an essential system for renal disposition of cationic and anionic drugs, respectively. Our recent publications and current preliminary results indicate a broad effect by chronic Cd exposure on renal transporters including OCTs, MATEs, OATs and MRPs. However, the detail mechanism of transporter regulation by Cd and its broad impact on drug disposition and response remain to be illustrated. We hypothesize that chronic Cd exposure could alter renal transporter function, resulting in alteration in drug disposition and toxicity in the kidney. To test this hypothesis, we propose to conduct research with three specific Aims. Firstly, by using a variety of cellular and molecular assays, along with proteomic approach, we will uncover a molecular mechanism by which chronic Cd exposure enhances the translocation of OCT and OAT uptake proteins from the cytoplasmic pool to cell membrane and consequently increase the cellular accumulation of small molecules that are the substrates of these transporters (Aim 1). Most clinical used drugs are either organic cations or organic anions. We then propose to demonstrate the impact of Cd exposure on the disposition of cationic drugs by investigating the effects of Cd exposure on OCT and MATE expression in mouse kidney tissues and human renal cells, and particularly the impact on cisplatin disposition and nephrotoxicity using Oct1/2- and Mate1-deficinet mice (Aim 2). Lastly, the effects of chronic Cd exposure on expression of the anionic drug transporters OATs and MRPs will be characterized in mouse kidney tissues and human renal cells, and specifically Cd impact on the disposition and nephrotoxicity of the antiviral tenofovir will be studied with Oat1/3-, Mrp4-deficient mice and OAT pharmacological inhibition (Aim 3). Successful completion of this project will provide a foundation to uncover environmental Cd as a previously unrecognized factor for the broad variation in drug disposition and response, contributing to a better drug theray.