Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced nephrotoxicity.
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 transporters have been thought to mediate CER uptake by the proximal tubule. The purpose 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 expressing rat OAT1 (S3 rOAT1) was established and used in this study. The cellular uptake of [14C]-para-aminohippuric acid (PAH), a prototype organic anion, and that of [14C]-CER were measured. The effects of CER on the viability of the cells and the amount of lipid peroxidation were estimated.


RESULTS
S3 rOAT1 expressed a functional organic anion transporter in the cytoplasmic membrane, and exhibited CER uptake activity. CER treatment resulted 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 transfected with an expression vector lacking the rOAT1 insert. Probenecid, an inhibitor of organic anion transport, and probucol, an antioxidant, significantly suppressed the decrease in viability and increase in the amount of lipid peroxidation in S3 rOAT1 treated with CER. The effects of various cephalosporin antibiotics on the uptake of [14C]PAH were correlated significantly with the effects of these drugs on cell viability.


CONCLUSIONS
These results suggest that rOAT1 is, at least in part, responsible for the cellular uptake of CER and therefore CER-induced nephrotoxicity.
Takeda
M
M
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan.
Tojo
A
A
Sekine
T
T
Hosoyamada
M
M
Kanai
Y
Y
Endou
H
H
D000818:Animals; D027321:Anion Transport Proteins; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D001692:Biological Transport / Q000235:genetics; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002509:Cephaloridine / Q000493:pharmacokinetics / Q000633:toxicity*; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000633:toxicity*; D018076:DNA, Complementary; D007674:Kidney Diseases / Q000139:chemically induced*; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis / Q000502:physiology; D011339:Probenecid / Q000494:pharmacology; D011341:Probucol / Q000494:pharmacology; D014528:Uricosuric Agents / Q000494:pharmacology; D010130:p-Aminohippuric Acid / Q000493:pharmacokinetics
D027321:Anion Transport Proteins; D000924:Anticholesteremic Agents; D000952:Antigens, Polyomavirus Transforming; D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D002511:Cephalosporins; D018076:DNA, Complementary; D014528:Uricosuric Agents; D002509:Cephaloridine; D011341:Probucol; D011339:Probenecid; D010130:p-Aminohippuric Acid