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Evidence has shown that cytochrome P450 2E1 (CYP2E1), a drug metabolism enzyme expressed in proximal tubules, mediates the production of reactive oxygen species during cisplatin-induced injury. Previously, we showed that the repurposed drug 4-methylpyrazole (4MP) blocks CYP2E1 activity. Here, we investigated the potential protective effects of 4MP against CIN. Male and female C57BL\/6J mice were treated intraperitoneally (i.p.) with a single 20\u2009mg\/kg dose of cisplatin for 3\u2009days or 9\u2009mg\/kg\/wk for 4\u2009wk with or without 50\u2009mg\/kg 4MP as a co-treatment. Our findings revealed that acute treatment with cisplatin induced severe histological tubular damage and elevated plasma BUN and creatinine levels in male but not female mice. This difference correlated with higher basal CYP2E1 expression in the kidneys of male mice compared with female mice. We also found that cisplatin increased renal CYP2E1 activity and that inhibition of CYP2E1 with 4MP significantly reduced cisplatin-induced cell death in male mice and primary normal human kidney cells. By contrast, human bladder cancer cells do not express CYP2E1, and treatment with 4MP did not interfere with cisplatin\u2019s anticancer effects in human bladder cancer HTB9 cells. This study highlights the critical role of CYP2E1 in CIN and suggests that its inhibition with 4MP in the kidney is a potential prophylactic therapeutic option to prevent CIN in bladder cancer patients without affecting its antineoplastic effect.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaf053","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T19:28:26Z","timestamp":1746041306000},"page":"4-18","source":"Crossref","is-referenced-by-count":6,"title":["4-Methylpyrazole-mediated inhibition of cytochrome P450 2E1 protects renal epithelial cells, but not bladder cancer cells, from cisplatin toxicity"],"prefix":"10.1093","volume":"206","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5324-1164","authenticated-orcid":false,"given":"Jephte Y","family":"Akakpo","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center , Kansas City, KS 66160,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Abbott","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Kansas Medical Center , Kansas City, KS 66160,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin L","family":"Woolbright","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, University of Kansas Medical Center , Kansas City, KS 66160,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5438-2409","authenticated-orcid":false,"given":"Anup","family":"Ramachandran","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center , Kansas City, KS 66160,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick G","family":"Schnellmann","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, R. Ken Coit College of Pharmacy, University of Arizona , Tucson, AZ 66160,","place":["United States"]},{"name":"Coit Center for Longevity and Neurotherapeutics, R. Ken Coit College of Pharmacy, University of Arizona , Tucson, AZ 85719,","place":["United States"]},{"name":"BIO5 Institute, College of Medicine, University of Arizona , Tucson, AZ 85719,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren P","family":"Wallace","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Kansas Medical Center , Kansas City, KS 66160,","place":["United States"]},{"name":"Jared Grantham Kidney Institute, University of Kansas Medical Center , Kansas City, KS 66160,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Kansas Medical Center , Kansas City, KS 66160,","place":["United States"]},{"name":"Department of Cancer Biology, University of Kansas Medical Center , Kansas City, KS 66160,","place":["United 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