Influence of Oct1/Oct2-deficiency on cisplatin-induced changes in urinary N-acetyl-beta-D-glucosaminidase.
OBJECTIVE
This study aimed to test the influence of functional renal organic cation transporters (OCT2 in humans, Oct1 and Oct2 in mice) on biomarkers of cisplatin nephrotoxicity, such as urinary activity of N-acetyl-beta-D-glucosaminidase (NAG).


METHODS
Temporal cisplatin-induced nephrotoxicity was assessed by histopathology and biomarkers. Cisplatin-mediated NAG changes and survival were determined in wild-type and Oct1/2(-/-) mice. Identification of OCT2 inhibitors was done in transfected 293Flp-In cells, and the NCI(60) cell line panel was used to assess contribution of OCT2 to cisplatin uptake in cancer cells.


RESULTS
Classical biomarkers such as blood urea nitrogen and serum creatinine were not elevated until 72 hours after cisplatin administration and substantial kidney damage had occurred. Oct1/2(-/-) mice had 2.9-fold lower NAG by 4 hours (P < 0.0001) and 2.3-fold increased survival (P = 0.0097). Among 16 agents, cimetidine strongly inhibited uptake of tetraethylammonium bromide (P = 0.0006) and cisplatin (P < 0.0001), but did not have an influence on cisplatin uptake in SK-OV-3 cells, the cancer line with the highest OCT2 mRNA levels. In wild-type mice, cimetidine inhibited cisplatin-induced NAG changes (P = 0.016 versus cisplatin alone) to a degree similar to that seen in Oct1/2(-/-) mice receiving cisplatin (P = 0.91). Cumulative NAG activity of >0.4 absorbance units (AU) was associated with 21-fold increased odds for severe nephrotoxicity (P = 0.0017), which was linked with overall survival (hazard ratio, 8.1; 95% confidence interval, 2.1-31; P = 0.0078).


CONCLUSIONS
Cimetidine is able to inhibit OCT2-mediated uptake of cisplatin in the kidney, and subsequently ameliorate nephrotoxicity likely with minimal effect on uptake in tumor cells.
Franke
Ryan M
RM
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Kosloske
Ashley M
AM
Lancaster
Cynthia S
CS
Filipski
Kelly K
KK
Hu
Chaoxin
C
Zolk
Oliver
O
Mathijssen
Ron H
RH
Sparreboom
Alex
A
D000118:Acetylglucosaminidase / Q000652:urine*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D015415:Biomarkers / Q000032:analysis; D045744:Cell Line, Tumor; D002927:Cimetidine / Q000494:pharmacology; D002945:Cisplatin / Q000378:metabolism / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050811:Octamer Transcription Factor-1 / Q000172:deficiency*; D027701:Organic Cation Transport Proteins / Q000172:deficiency*; D000075102:Organic Cation Transporter 2; D016133:Polymerase Chain Reaction
D000970:Antineoplastic Agents; D015415:Biomarkers; D004791:Enzyme Inhibitors; D050811:Octamer Transcription Factor-1; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C494166:Pou2f1 protein, mouse; C491012:Slc22a2 protein, mouse; D002927:Cimetidine; D000118:Acetylglucosaminidase; D002945:Cisplatin