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Attenuation of cisplatin nephrotoxicity by inhibition of soluble epoxide hydrolase

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Abstract

Cisplatin is a highly effective chemotherapeutic agent against many tumors; however, it is also a potent nephrotoxicant. Given that there have been no significant advances in our ability to clinically manage acute renal failure since the advent of dialysis, the development of novel strategies to ablate nephrotoxicity would represent a significant development. In this study, we investigated the ability of an inhibitor of soluble epoxide hydrolase (sEH), n-butyl ester of 12-(3-adamantan-1-yl-ureiido)-dodecanoic acid (nbAUDA), to attenuate cisplatin-induced nephrotoxicity. nbAUDA is quickly converted to AUDA and results in maintenance of high AUDA levels in vivo. Subcutaneous administration of 40 mg/kg of nbAUDA to C3H mice every 24 h resulted in elevated blood levels of AUDA; this protocol was also associated with attenuation of nephrotoxicity induced by cisplatin (intraperitoneal injection) as assessed by BUN levels and histological evaluation of kidneys. This is the first report of the use of sEH inhibitors to protect against acute nephrotoxicity and suggests a therapeutic potential of these compounds.

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Acknowledgments

This work was supported by a grant from the Texas A&M University Vice President for Research (ARP) and NIEHS Grants ES02710 and P42 ES04699, NIH/NHLBI grant R01 HL59699-06A1 (BDH).

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Authors and Affiliations

  1. Department of Systems Biology and Translational Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX, 77843, USA

    Alan R. Parrish & Gang Chen

  2. Department of Veterinary Integrated Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX, USA

    Robert C. Burghardt

  3. Food and Drug Safety Center, Hatano Research Institute, 729-5 Ochiai, Hadano, Kanagawa, Japan

    Takaho Watanabe

  4. Department of Entomology and UCD Cancer Center, University of California at Davis, Davis, CA, USA

    Takaho Watanabe, Christophe Morisseau & Bruce D. Hammock

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  1. Alan R. Parrish
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  2. Gang Chen
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  3. Robert C. Burghardt
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  4. Takaho Watanabe
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  5. Christophe Morisseau
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  6. Bruce D. Hammock
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Correspondence to Alan R. Parrish.

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Parrish, A.R., Chen, G., Burghardt, R.C. et al. Attenuation of cisplatin nephrotoxicity by inhibition of soluble epoxide hydrolase. Cell Biol Toxicol 25, 217–225 (2009). https://doi.org/10.1007/s10565-008-9071-0

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  • DOI: https://doi.org/10.1007/s10565-008-9071-0

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