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Differences in susceptibility of cisplatin (CDDP) induced toxicity in human versus rat proximal tubular cell lines
Author(s) -
Sarangarajan Rangaprasad,
Cacini William
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1139-a
Subject(s) - toxicity , cisplatin , chemistry , incubation , cell culture , pharmacology , cytotoxicity , tetraethylammonium , biochemistry , in vitro , biology , chemotherapy , genetics , organic chemistry , potassium
The mechanism by which CDDP enters kidney and induces toxicity is unclear. This study used immortalized proximal tubular cell lines from normal human (HK‐2) and rat (NRK‐52E) sources to compare the role of organic cation transporter (OCT) and organic anion transporter (OAT) in CDDP‐ induced renal uptake and toxicity. Tetraethylammonium (TEA) and p‐aminohippuric acid (PAH), prototypical substrates of OCT and OAT respectively, were used as competitive inhibitors of cisplatin uptake. Toxicity was determined using CellTiter96AQ ueous One Solution cell proliferation assay (Promega) in the presence or absence of CDDP. Incubation of HK‐2 and NRK‐52E cells lines with increasing concentrations of CDDP for up to 72 hours resulted in dose & time dependent increase in CDDP induced toxicity. Interestingly, between 50–250μM concentration, HK‐2 cells were more resistant to CDDP toxicity compared to NRK‐52E cells. Preincubation with either 100μM TEA or 100μM PAH followed by 48 hour co‐incubation with increasing concentrations of CDDP did not confer protection to HK‐2 cells. In contrast, preincubation with 100μM TEA or 100μM PAH followed by co‐incubation with CDDP significantly reduced toxicity in NRK‐52E cells, in particular at the 20μM concentration. The results demonstrate that (a) NRK‐52E cells are clearly more sensitive to CDDP‐ induced toxicity compared to HK‐2 cells and (b) presence of either OCT or OAT substrates can significantly reduce toxicity of CDDP in NRK‐52E cells at low concentrations but not in HK‐2 cells.