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Identification of OAT1/OAT3 as Contributors to Cisplatin Toxicity
S Hu1, A F Leblanc1, A A Gibson1
1Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
Abstract:
Cisplatin is among the most widely used anticancer drugs and known to cause a dose-limiting nephrotoxicity, which is partially dependent on the renal uptake carrier OCT2. We here report a previously unrecognized, OCT2-independent pathway of cisplatin-induced renal injury that is mediated by the organic anion transporters OAT1 and OAT3. Using transporter-deficient mouse models, we found that this mechanism regulates renal uptake of a mercapturic acid metabolite of cisplatin that acts as a precursor of a potent nephrotoxin. The function of these two transport systems can be simultaneously inhibited by the tyrosine kinase inhibitor nilotinib through noncompetitive mechanisms, without compromising the anticancer properties of cisplatin. Collectively, our findings reveal a novel pathway that explains the fundamental basis of cisplatin-induced nephrotoxicity, with potential implications for its therapeutic management.
Insights
A new pathway for cisplatin kidney damage involving organic anion transporters (OAT1/OAT3) has been discovered. This finding offers potential strategies to reduce chemotherapy
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Cisplatin is a vital chemotherapy agent but causes dose-limiting kidney toxicity.
- This nephrotoxicity is partly mediated by the organic cation transporter 2 (OCT2).
- A comprehensive understanding of all cisplatin-induced renal injury pathways is crucial.
Purpose of the Study:
- To identify and characterize novel pathways of cisplatin-induced nephrotoxicity.
- To investigate the role of organic anion transporters (OAT1 and OAT3) in cisplatin nephrotoxicity.
- To explore potential therapeutic interventions targeting these newly identified pathways.
Main Methods:
- Utilized transporter-deficient mouse models to assess renal injury mechanisms.
- Analyzed the renal uptake of cisplatin metabolites.
- Investigated the inhibitory effects of nilotinib on OAT1 and OAT3 function.
Main Results:
- Identified an OCT2-independent pathway for cisplatin nephrotoxicity mediated by OAT1 and OAT3.
- Demonstrated that a mercapturic acid metabolite of cisplatin, processed via OAT1/OAT3, is a precursor to a nephrotoxin.
- Showed that nilotinib non-competitively inhibits OAT1 and OAT3 without affecting cisplatin's anticancer efficacy.
Conclusions:
- Cisplatin-induced nephrotoxicity involves a previously unrecognized OAT1/OAT3-dependent pathway.
- Targeting OAT1 and OAT3 with inhibitors like nilotinib may mitigate cisplatin nephrotoxicity.
- These findings provide a new basis for managing cisplatin-induced kidney damage in cancer patients.
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