PT  - JOURNAL ARTICLE
AU  - Dantzler, William H.
AU  - Evans, Kristen K.
AU  - Groves, Carlotta E.
AU  - Welborn, John R.
AU  - North, Jason
AU  - Stevens, James L.
AU  - Wright, Stephen H.
TI  - Relation of Cysteine Conjugate Nephrotoxicity to Transport by the Basolateral Organic Anion Transport System in Isolated S2 Segments of Rabbit Proximal Renal Tubules
DP  - 1998 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 52--60
VI  - 286
IP  - 1
4099  - http://jpet.aspetjournals.org/content/286/1/52.short
4100  - http://jpet.aspetjournals.org/content/286/1/52.full
SO  - J Pharmacol Exp Ther1998 Jul 01; 286
AB  - 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-cysteinecis-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 ofl-phenylalanine had little effect. High concentrations ofS-(2-benzothiazole)-l-cysteine and para-aminohippurate in the bathing medium with DCVC inhibited the loss of 86Rb (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 86Rb 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. The American Society for Pharmacology and Experimental Therapeutics