THE ROLE OF TRANSPORT IN CHEMICAL NEPHROTOXICITY

Various physiologic factors play a role in determining the extent of c hemical-induced nephrotoxicity. One such factor relates to the transpo rt systems that exist in the kidney. Several examples can be given of organic substances that are nephrotoxic only after being transported i nto renal tubular cells. Some of the cephalosporin antibiotics have be en shown to produce proximal tubular necrosis after transport into tho se cells. Blockade of transport by competitors eliminates or reduces t he nephrotoxic response. Citrinin, a secondary product of fungal metab olism, also produces proximal tubular necrosis, but only after transpo rt into proximal tubular cells. Both the cephalosporins and citrinin u tilize the organic anion transporter for entry into the cells, a trans porter present in adult animals of all species and probably important physiologically for moving metabolic substrates into cells. Various gl utathione conjugates (e.g., S-(1,2-dichlorovinyl) glutathione [DCVG]) also are transported into proximal tubular cells with a resulting neph rotoxicity. DCVG utilizes the sodium-dependent transport process that moves glutathione into proximal tubular cells, a process that is inhib ited by probenecid. Finally, certain heavy metals also are transported into renal tubular cells. For example, mercuric ion enters proximal c ells both from the luminal and peritubular sides and sulfhydryl compou nds modify the transport. Movement of mercury from the peritubular sid e of the cell may be modified by certain organic anions. The character istics of these mechanisms are less well understood than the mechanism s for the organic compounds.