Relation of Cysteine Conjugate Nephrotoxicity to Transport by the Basolateral Organic Anion Transport System in Isolated S2 Segments of Rabbit Proximal Renal Tubules

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 286; no. 1; p. 52
• Main Authors: Dantzler, W H, Evans, K K, Groves, C E, Welborn, J R, North, J, Stevens, J L, Wright, S H
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.07.1998
• Subjects: Animals; Anion Transport Proteins; Biological Transport; Carrier Proteins - physiology; Cysteine - analogs & derivatives; Cysteine - metabolism; Cysteine - toxicity; In Vitro Techniques; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Probenecid - pharmacology; Rabbits; Rubidium Radioisotopes - metabolism
• ISSN: 0022-3565; 1521-0103

We examined basolateral transport of the radiolabeled zwitterionic nephrotoxic cysteine S -conjugate, S -(1,2-dichlorovinyl)- l -cysteine (DCVC), inhibition of such transport and the effects of inhibition of transport on the toxicity produced by DCVC in isolated S2 segments of rabbit proximal tubules. High concentrations of unlabeled DCVC itself and an unlabeled nontoxic cysteine S -conjugate, S -(2-benzothiazole)- l -cysteine cis -inhibited the basolateral uptake of radiolabeled DCVC by ∼80 to 85%. High concentrations of para-aminohippurate, the prototype substrate for the basolateral organic anion transport system, and probenecid, a well-known inhibitor of basolateral organic anion transport, cis -inhibited the basolateral uptake of radiolabeled DCVC by ∼70%, whereas a high concentration of l -phenylalanine had little effect. High concentrations of S -(2-benzothiazole)- l -cysteine and para-aminohippurate in the bathing medium with DCVC inhibited the loss of 86 Rb (used as a K + surrogate to measure toxicity) from S2 segments produced by DCVC alone to approximately the same extent as they inhibited uptake of DCVC. Under the same circumstances, probenecid completely inhibited 86 Rb loss. These data indicate that in rabbit proximal renal S2 tubules basolateral entry of DCVC can occur to a major extent via the organic anion transport pathway and that inhibition of such entry can reduce toxicity to approximately the same extent that entry is reduced. They also suggest that probenecid provides additional protection from DCVC toxicity.