Akakpo Jephte Y, Abbott Erika, Woolbright Benjamin L, Ramachandran Anup, Schnellmann Rick G, Wallace Darren P, Taylor John A
Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, United States.
Department of Urology, University of Kansas Medical Center, Kansas City, KS 66160, United States.
Toxicol Sci. 2025 Jul 1;206(1):4-18. doi: 10.1093/toxsci/kfaf053.
Cisplatin is an effective chemotherapeutic drug for the treatment of bladder cancer, though cisplatin-induced nephrotoxicity (CIN) occurs in ∼20% to 30% of patients, limiting its clinical use. 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 mg/kg dose of cisplatin for 3 days or 9 mg/kg/wk for 4 wk with or without 50 mg/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's 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.
顺铂是一种治疗膀胱癌的有效化疗药物，不过约20%至30%的患者会出现顺铂诱导的肾毒性（CIN），这限制了其临床应用。有证据表明，细胞色素P450 2E1（CYP2E1）是一种在近端小管中表达的药物代谢酶，在顺铂诱导的损伤过程中介导活性氧的产生。此前，我们发现重新利用的药物4-甲基吡唑（4MP）可阻断CYP2E1的活性。在此，我们研究了4MP对CIN的潜在保护作用。对雄性和雌性C57BL/6J小鼠进行腹腔注射（i.p.），给予单次20mg/kg剂量的顺铂，持续3天，或给予9mg/kg/周剂量的顺铂，持续4周，同时或不同时联合50mg/kg的4MP进行共处理。我们的研究结果显示，顺铂的急性处理在雄性而非雌性小鼠中诱导了严重的组织学肾小管损伤，并提高了血浆尿素氮和肌酐水平。这种差异与雄性小鼠肾脏中基础CYP2E1表达高于雌性小鼠有关。我们还发现顺铂增加了肾脏CYP2E1的活性，并且用4MP抑制CYP2E1可显著降低顺铂诱导的雄性小鼠和原代正常人肾细胞的细胞死亡。相比之下，人膀胱癌细胞不表达CYP2E1，用4MP处理不会干扰顺铂对人膀胱癌细胞HTB9的抗癌作用。这项研究突出了CYP2E1在CIN中的关键作用，并表明在肾脏中用4MP抑制它是一种潜在的预防性治疗选择，可在不影响其抗肿瘤作用的情况下预防膀胱癌患者的CIN。
