Recent advances in molecular mechanisms of nephrotoxicity

Numerous drugs and endogenous compounds are efficiently excreted from the renal proximal tubule via two carrier-mediated pathways, that are organic anion and organic cation transport systems. Since most nephrotoxicants are taken up into renal target cells for further actions, these transport systems seem to be an early event for nephrotoxicity. Recent advances in nephrotoxicity are molecular cloning of several transporters related to important toxic compounds in the kidney. An organic cation transporter 1 (OCT1) was cloned in 1994. On the other hand, we recently isolated a complementary DNA that encodes an organic anion transporter 1 (OAT1) as an anion/dicarboxylate exchanger of the basolateral membrane of proximal tubule. Transepithelial secretion of organic anion consists of an influx of anionic substrates into the cell through the basolateral membrane and their efflux to the urine across the apical membrane. OAT1 displays a remarkably wide substrate specificity, including endogenous substrates, a variety of drugs with different structures and natural toxins. We further isolated homologs of OAT series such as liver-specific OAT2 and kidney-, liver- and brain-expressing OAT3. Because the amino acid sequence of OAT1 shows 38% identity to OCT1, a newly defined 'multispecific organic ion transporter superfamily' will provide potential tools to assess mechanisms of many nephrotoxicants including drugs and xenobiotics, and contribute also in understanding more precisely nephrotoxic mechanisms of chemicals.