title: Change in soluble epoxide hydrolase (sEH) during cisplatin-induced acute renal failure in mice.
abstract: Cisplatin is one of the most effective chemotherapeutic agents against various types of cancers; however, it is also associated with nephrotoxicity. Recently, it was reported that inflammatory mechanisms play a key role in the development of nephrotoxicity. Epoxyeicosatrienoic acids (EETs) have an anti-inflammatory effect and are metabolized by soluble epoxide hydrolase (sEH: encoded by EPHX2 gene). Here, we determined the change in sEH activity and EPHX2 expression in renal tissue associated with the development of cisplatin-induced nephrotoxicity. Cisplatin administration decreased hydrolase activity accompanied by down-regulation of sEH and EPHX2 expression. The down-regulation occurred prior to the elevation of blood urea nitrogen (BUN) and tumor necrosis factor-α (TNF-α) gene expression or at treatment with low dose cisplatin. In addition, a negative correlation was found between EPHX2 expression and renal thiobarbituric acid reactive substance (TBARS), and edaravone, a radical scavenger, administration did not down-regulate expression of this gene. The results of this study suggest that cisplatin decreased sEH activity through the down-regulation of sEH and EPHX2 expression, and this down-regulation was involved in a negative feedback loop to protect renal tissue from further damage. Thus, sEH is a potential therapeutic target of cisplatin-induced nephrotoxicity.
authors.affiliation: Division of Pharmacology, Department of Pharmacology, Toxicology & Therapeutics, School of Pharmacy, Showa University.
authors.forename: Terumasa
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Yang-Il
authors.initials: YI
authors.lastname: Fang
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Ohata
authors.forename: Kazuo
authors.initials: K
authors.lastname: Honda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D015536:Down-Regulation / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000235:genetics* / Q000378:metabolism*; D025461:Feedback, Physiological; D015870:Gene Expression / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008815:Mice, Inbred Strains; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D017392:Thiobarbituric Acid Reactive Substances; D004851:Epoxide Hydrolases; D002945:Cisplatin