El-Dessouki Ahmed M, Yousef Eman H, Raslan Nahed A, Alwakeel Asmaa I, Ibrahim Samar, Alzokaky Amany A
Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, Giza, 12566, Egypt.
Pharmacology and Biochemistry Department, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Feb 14. doi: 10.1007/s00210-025-03808-6.
Doxorubicin (DOX) is a highly potent broad-spectrum anticancer drug, but it has severe side effects, including hepatotoxicity. Therefore, we evaluated the efficacy of febuxostat (FBX), a specific inhibitor of xanthine oxidase and antioxidant, in blocking hepatotoxicity associated with DOX in rats. Rats were treated with FBX (10 or 15 mg/kg/day orally for 2 weeks) and given DOX (15 mg/kg as single dose at the 7th day, intraperitoneal) to induce hepatotoxicity. The results indicated that FBX could reduce the pathological alterations of liver tissues induced by DOX and ameliorate the inappropriate changes in liver function biomarkers (AST, ALT, and ALP) in serum, oxidative stress parameters (catalase, superoxide dismutase, NOX1, NQO-1, HO-1, Keap-1, and Nrf2) and inflammatory markers in the liver (NF-κB p65, TNF-α, NLRP3). Additionally, FBX attenuated the p53, BAX, cytochrome C, caspase-9, and caspase-3 levels to restrain cell apoptosis. In addition, FBX therapy was found to increase protein levels of SIRT-1 and AMPK in the liver. These findings demonstrate that FBX can reduce the hepatotoxicity caused by DOX in rats through mechanisms that counteract oxidative stress, inflammation, and apoptosis.
阿霉素（DOX）是一种高效的广谱抗癌药物，但它具有严重的副作用，包括肝毒性。因此，我们评估了非布索坦（FBX）（一种黄嘌呤氧化酶特异性抑制剂和抗氧化剂）在阻断大鼠DOX相关肝毒性方面的疗效。给大鼠口服FBX（10或15毫克/千克/天，持续2周），并在第7天腹腔注射DOX（15毫克/千克单剂量）以诱导肝毒性。结果表明，FBX可以减轻DOX诱导的肝组织病理改变，并改善血清中肝功能生物标志物（AST、ALT和ALP）、氧化应激参数（过氧化氢酶、超氧化物歧化酶、NOX1、NQO-1、HO-1、Keap-1和Nrf2）以及肝脏中炎症标志物（NF-κB p65、TNF-α、NLRP3）的异常变化。此外，FBX降低了p53、BAX、细胞色素C、caspase-9和caspase-3的水平以抑制细胞凋亡。此外，发现FBX治疗可增加肝脏中SIRT-1和AMPK的蛋白质水平。这些发现表明，FBX可以通过对抗氧化应激、炎症和凋亡的机制降低大鼠DOX引起的肝毒性。
