Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced nephrotoxicity

Background. Cephaloridine(CER) has been used to elucidate the mechanisms of cephalosporin antibiotic-induced nephrotoxicity. Organic anion transporter s have been thought to mediate CER uptake by the proximal tubule. The purpo se of this study was to elucidate the possible involvement of organic anion transporter 1 (OAT1) in CER-induced nephrotoxicity. Methods. A mouse terminal proximal straight tubule (S3) cell line stably ex pressing rat OAT1 (S3 rOAT1) was established and used in this study. The ce llular uptake of [C-14]-para-amino-hippuric acid (PAH), a prototype organic anion, and that of [C-14]-CER were measured. The effects of CER on the via bility of the cells and the amount of lipid peroxidation were estimated. Results. S3 rOAT1 expressed a functional organic anion transporter in the c ytoplasmic membrane, and exhibited CER uptake activity. CER treatment resul ted in a more significant decrease in the viability and a more significant increase in the amount of lipid peroxidation in S3 rOAT1 than in S3 cells t ransfected with an expression vector lacking the rOAT1 insert. Probenecid, an inhibitor of organic anion transport, and probucol, an antioxidant, sign ificantly suppressed the decrease in viability and increase in the amount o f lipid peroxidation in S3 rOAT1 treated with CER. The effects of various c ephalosporin antibiotics on the uptake of [C-14]PAH were correlated signifi cantly with the effects of these drugs on cell viability. Conclusions. These results suggest that rOAT1 is, at least in part, respons ible for the cellular uptake of CER and therefore CER-induced nephrotoxicit y.