Attenuation of cisplatin nephrotoxicity by inhibition of soluble epoxide hydrolase.
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.
Parrish
Alan R
AR
Department of Systems Biology and Translational Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX 77843, USA. parrish@medicine.tamhsc.edu
Chen
Gang
G
Burghardt
Robert C
RC
Watanabe
Takaho
T
Morisseau
Christophe
C
Hammock
Bruce D
BD
D000218:Adamantane / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001806:Blood Urea Nitrogen; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000633:toxicity*; D004336:Drug Antagonism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D007279:Injections, Subcutaneous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D007850:Lauric Acids / Q000032:analysis / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
C504897:12-(3-adamantan-1-ylureido)dodecanoic acid; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007850:Lauric Acids; D004851:Epoxide Hydrolases; D000218:Adamantane; D002945:Cisplatin